- Email: [email protected]
Correcting a decade of negative news about mammography
Clinical Imaging xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Breast Imaging
Correcting a decade of negative news about mammography Elaine Schattner Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College, New York, NY 10021, United States of America
1. Introduction It's been ten years since the U.S. Preventive Services Task Force (USPSTF) pulled back on recommendations for breast cancer screening of women ages 40–49 years [1]. When the controversy broke in November 2009 [2–4], I had recently completed a master's degree in journalism. The news hit close for two reasons: I'd practiced oncology and seen the devastating effects of advanced disease; and because a superb radiologist had detected a small invasive tumor in my left breast when I was age 42. After surgery and a short course of chemotherapy, my prognosis was excellent. I considered myself lucky! While debate intensified [5–7], I followed closely—with a mix of fascination and concern [8,9]. As a physician, I was disturbed by how frequently false assumptions about factual subjects—ranging from breast cancer's incidence to women's psychology—played into nominally objective analyses published in top-tier medical journals. A flood of damaging reports amplified perceived risk of “overdiagnosis” and overtreatment. Study after flawed study—like a house of cards—touted mammography's alleged harms and costs [10–17]. “Mammography does more harm than good” sums up countless headlines. The revelation of mammography's imperfectness—the story of it having been oversold—drew readers and angry comments [18–24]. For a while, I was stunned by the volume of negative hype, and by some health editors' apparent exuberance over downbeat conclusions. As journalism was shifting from print to predominantly digital media, I wondered if the truth about modern screening, however complicated, mattered less than providing a counternarrative [25–28]. Women and primary care doctors are plenty aware of mammography's limits. A decade's worth of negative analyses and neat decision tools, based on archaic data [29–32], have persuaded many women to avoid, delay or deliberately skip getting screened [33–37]. In 2015, only 64% of U.S. women over age 40 reported having a mammogram within two years [38]. Since 2010, the proportion screened has been falling. After dropping and stabilizing, the average diameter of newlydiagnosed breast cancers has crept back above 2 cm [39]. Now I'm worried. In 2019, many doctors, journalists and advocates consider the matter settled—against mammography, particularly for women ages 40 - 49 years. Soon the USPSTF will again start updating its recommendations. The Task Force last published breast cancer screening guidelines in
January 2016 [40]. The multistep process, including public comments on the draft, takes over a year [41]. The next USPSTF review presents an opportunity to correct misinformation. Women deserve fair guidance about screening's risks and benefits. For this reason, the Agency for Healthcare Research and Quality (AHRQ), which controls USPSTF membership, should appoint doctors who are most knowledgeable about mammography, including radiologists, to the government panel along with primary care physicians, epidemiologists and public health experts. While concerns may arise about specialists' potential conflicts of interest, radiologists' knowledge is necessary to assure the panel is reasonably familiar with current technology and screening facts. Other experts who should participate include pathologists, surgeons, breast oncologists and patient advocates, because they have the most experience with breast cancer diagnosis, treatment and survivorship. 2. Problematic literature Errors cloud the literature on mammography [26,27,42–45]. Previously I've reported on the problematic reliance of seemingly recent studies on screens using outdated equipment [46]. For instance, the 2013 Cochrane review includes results from the 1960s [47]. An oftcited Canadian study examined outcomes after mammograms taken in five consecutive years during the mid-1980s [16]. Perhaps the dates wouldn't matter if mammography were a straightforward measure, like checking a sodium level or hemoglobin. But imaging technology has advanced! Consider how cell phones and cameras have improved since 1985. Would you choose a device today based on a 1990 summary? Of course not! Yet investigators continue plugging old findings into fresh reports and decision aides [48–50]. Incorrect assumptions undermine conclusions from observational studies. Among the most egregious mistakes is the constant underlying disease burden assumed by Welch and colleagues [51]. After noting that metastatic breast cancer rates did not drop in the mammography era, they infer that screening must be ineffective [51–54]. However, Welch and colleagues fail to account for the increasing baseline rate of disease: from 1975 to 2015, the overall incidence of invasive breast cancers rose by approximately 25% among U.S. women [54]. Given this upward trend, an alternative conclusion can be drawn: Without mammography, advanced tumors would be more frequent [55,56]. Other
E-mail addresses: [email protected], [email protected]. https://doi.org/10.1016/j.clinimag.2019.03.011 Received 15 January 2019; Received in revised form 7 March 2019; Accepted 25 March 2019 0899-7071/ © 2019 Published by Elsevier Inc.
Please cite this article as: Elaine Schattner, Clinical Imaging, https://doi.org/10.1016/j.clinimag.2019.03.011
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
investigators, by adjusting for changes in the underlying disease rate, have found a relative reduction in metastatic cases [57]. In general, the anti-screening literature ignores 30 years of progress in radiology and pathology. “Overdiagnosis” cannot be directly measured. Many reports conflate overdiagnosis—a concept—and overtreatment [17,58–60], which indeed causes harm and can be prevented by educating doctors and patients, so they don't overreact to small tumors [61]. Other problems include crossover effects between study arms of randomized trials. Physicians and economists have, so far, failed to weigh and report on the consequences of delayed breast cancer diagnosis [45,61].
Temporal trends in U.S. breast cancer mortality, women ages 40+, 1969-2016 80
1989 Rate, 74.0 per 100,000 Women
70 -40%
60 50 2016 Rate, 44.6 per 100,000 Women
40 30
3. Concerning sources
20
It is troubling that so many high-profile papers were authored by a few individuals. Dr. H. Gilbert Welch, a family physician who was a professor at Dartmouth, resigned in 2018 after the university determined that he had committed plagiarism [62]. Welch wrote a popular book and numerous op-ed pieces about overdiagnosis [59,63–65]. Journalists quoted him. In talks and YouTube videos, Welch promoted theories that as many as 1 in 5 breast cancers can regress without treatment [66,67]. He suggested that breast cancer is a disease of affluence [68]. If someone commits plagiarism their conclusions may still be true. The same goes for a criminal physician such as Dr. David Newman, an emergency room doctor, former professor, and screening opponent [69,70]. Newman impressed leadership of the Association of Health Care Journalists and argued against mammography in The New York Times [71]. His book, Hippocrates' Shadow, was printed in multiple editions and translated [72]. He founded theNNT.com website—a “clearinghouse” [73] for data on the Number Needed to Treat [74], a statistical tool to inform medical decisions. TheNNT.com summary on screening mammography states: “None were helped.” Until 2016, he was active on social media, but his accounts have been removed.1 In 2017, he was sentenced to jail for sexually assaulting female patients [75]. Another influential anti-mammographer, Dr. Peter Gøtzsche, was recently expelled from the Cochrane Collaboration [76,77], a prestigious organization that reviews medical evidence. The uproar had to do with his concerns about human papillomavirus vaccination. Over two decades, Gøtzsche published over eighty papers on screening [78]. His book, Mammography Screening: Truth, Lies and Controversy, contains a forward by the president of the National Breast Cancer Coalition; she reflects on when Gøtzsche spoke before a large audience of patient advocates [79]. He is first author of the 2013 Cochrane review which assumes “overdiagnosis and overtreatment is at 30%” and harps on women's psychological distress from screening [47]. Each of these individuals has had an immeasurable sway on how people view mammography. Perhaps the greater point is that everyone should be skeptical of all information and sources, including reports in major medical journals and books.
10 0 1969
1979
1989
1999
2009
2019
Fig. 1. Age-adjusted U.S. Breast Cancer Mortality Rates, Women Ages 40+, 1969–2016 (graph courtesy R. E. Hendrick, Ph.D.); Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality - All COD, Aggregated Total U.S. (1969–2016) < Katrina/Rita Population Adjustment > , National Cancer Institute, DCCPS, Surveillance Research Program, released December 2018. Underlying mortality data provided by NCHS (www.cdc.gov/nchs).
I believe that breast cancer is an urgent public health concern. This disease remains a leading killer of middle-aged women. Rates are increasing globally, including in poor countries [84]. In the United States, breast cancer is one of few malignancies with increasing incidence [85,86]. The rise is particularly steep among African American women [87]. Tragically, many patients present with advanced disease that might have been found at earlier stage: The concept of “underdiagnosis” should be considered. Abandoning mammography now—with the disease rate on the up—would be catastrophic to women's health. Rather, physicians and advocates need be informed of current evidence supporting screening's clinical benefit. The most powerful data are correlative: From 1989 to 2016—coincident with widespread uptake of mammography—mortality from breast cancer fell by 40% in the United States [86]. Among women over age 40 years, the death rate stayed constant from the late 1960s until 1989, when it began a steady decline (Fig. 1) [88,89]. This progress occurred despite a rising incidence of invasive cases [86]. Treatment advances cannot simply account for such a steep drop in the death rate, because metastatic disease remains incurable [90]. Rather, screening plays a significant role. In 2018, the NCI's Cancer Intervention and Surveillance Network (CISNET) confirmed that screening, combined with adjuvant therapy, is a major contributor to reducing breast cancer mortality in modern times. Using six distinct models developed at separate institutions, for 2012 the CISNET group attributed 37% of the lowering of deaths to screening. Of note, they found that screening confers a comparatively large reduction in mortality from aggressive breast cancer forms, such as Her2 positive and triple negative disease [91]. Most recently, an international group of researchers probed six decades of Swedish population registry data for fatal breast cancers. They observed a profound and durable reduction in breast cancer deaths among women who participated in mammography programs. In the first ten years after diagnosis, the risk of dying from breast cancer was 60% lower among screened than unscreened women; within 20 years after diagnosis, the risk was 47% lower [92]. These observations are not anecdotes (“a mammogram saved my life”), but statistically strong, population-based findings that support screening. Amid progress in molecular diagnostics and targeted therapy for breast cancer, clinical stage at diagnosis still holds a profound influence
4. Clarifying the picture Today, the anti-mammography campaign has so much traction that women's access to screening may be jeopardized. Influential physicians have proposed that routine mammography be stopped [80–83]. Since my diagnosis in 2002, a generation of young doctors has been educated in screening's harms, but without memory of an earlier era—when most breast cancer patients presented with palpable masses and later-stage disease. 1 Dr. Newman's influence is hard to gauge because his social media accounts have been removed; articles about his work appear to have been scrubbed from websites including journalistic outlets.
2
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
Long-term Outcomes Aer Estrogen Receptor Posive Breast Cancer
Fig. 2. A. Risk of distant recurrence (left) or death from breast cancer (right) 5, 10, 15 and 20 years after diagnosis, among 74,194 women with T1 or T2 Estrogen Receptor-positive disease scheduled to receive 5 years of endocrine therapy in a clinical trial, by pathological lymph node status. (Data source: N Engl J Med 2017; 377: 1836–46, Fig. 2.) B. Risk of distant recurrence 10, 15 and 20 years after diagnosis among 62,923 women with T1 (left) or T2 (right) breast cancer who initiated endocrine therapy within 5 years of enrolling in a clinical trial. (Data source: N Engl J Med 2017; 377: 1836–46, Fig. 3.)
on long-term outcomes. A 2017 report detailed recurrences and deaths among over 60,000 women with the most common form of breast cancer: estrogen-receptor (ER) positive (+) disease [93]. These investigators aimed to discern trends after endocrine therapy for earlystage (T1, ≤2 cm; and T2, 2–5 cm) disease; they did not intend to study screening. Nonetheless, a striking pattern emerged from this large analysis (Fig. 2). Twenty years after early-stage breast cancer, cumulative risk of distant (metastatic) recurrence ranged from 13%, after small node-negative cases, to 41% after tumors of 2–5 cm with 4–9 positive lymph nodes. For stage 3 breast cancer, not included in this paper, recurrence and death rates are even higher [94,95]. These findings indicate that the likelihood of recurrence or death from breast cancer is critically dependent on initial tumor stage: the smaller the better; the fewer lymph nodes involved, the better. As things stand, screening is the only way to detect breast cancer before it's so large that a woman or doctor might palpate the mass.
[97], particularly in elderly patients who are more likely to die from something else, the suggestion that it's preferable for a healthy woman to let breast cancer go unchecked until it's large enough that she feels a lump or experiences symptoms is foolish. A bitter source of misunderstanding is the fact that over 42,000 Americans will die from breast cancer this year [86]. Although diseasespecific mortality has fallen, the absolute number of deaths from breast cancer has been constant. This disconnect stems from the climbing baseline rate of invasive breast cancer—from 102 to 133 cases, in 1975 and 2015 respectively, per 100,000 adults [98]—in an expanding U.S. population. Causes of the rising incidence of breast cancer include aging, obesity and other factors warranting research [99]. While mammography is not foolproof, it's far better than some readers may be aware. In specialized radiology practices the pick-up rate (sensitivity) of mammography is around 85% [100]. With addition of breast ultrasound and other tools including MRI, screening's sensitivity surpasses 90%. Digital tomosynthesis, popularly known as 3D mammography, will further improve screening's accuracy [101], along with artificial intelligence. A pet peeve is the likening of breast tumors to barnyard animals such as birds, rabbits and turtles. These similes appear in news [102,103], magazine stories [104], radio [105], and YouTube videos
5. Correcting myths There is no evidence that breast cancer can vanish without treatment [96]. While slow-growing tumors don't necessarily cause harm 3
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
References2
[67,97]. If I were in the office of a physician who explained that I shouldn't get a mammogram because lethal tumors are like birds, which can't be caught, and turtle-type tumors are unlikely to kill me, I'd exit quickly. The barnyard pen theory of cancer and its capturability [106] has no relationship to actual pathology or medical science. The fact is, indolent tumors can be lethal. And most breast cancers, including faster-growing types, can be detected by mammography. A popular and divisive falsehood—widely shared on social media—is that “30%” of early-stage breast cancers recur after treatment. However, there is no modern evidence to support this statistic. Years ago, such as in the 1960s and 1970s, before screening and routine prescription of adjuvant therapy, recurrence rates were indeed higher. In 2018, a group of biostatisticians reported that in recent decades, 20% of early-stage patients, overall, experience recurrence within 20 years of diagnosis [95]. While worrying about late recurrence of hormonesensitive breast cancer is understandable, women would be wise to know that stage 1 tumors are less likely to recur than stage 3, and that most tumors—80%—don't come back [95]. Some doctors suggest that as treatments for breast cancer advance, the benefits of mammography diminish. But perhaps the opposite is true: If there were no effective remedies for early-stage disease, screening would be pointless.
[1] USPSTF. Screening For Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med 2009;151(10):716–26. [2] G. Kolata, Panel Urges Mammograms At 50, Not 40, The New York Times, November 16, 2009. [3] R. Siegel and M. Block, On Mammogram Recommendation, An Intense Debate, In: All Things Considered, NPR, November 19, 2009. [4] Cohen E. I Want My Mammograms!. CNN; November 19, 2009 Available from: http://web.archive.org/web/20181216061312/http://www.cnn.com/2009/ HEALTH/11/19/mammogram.guidelines.insurance/index.html. [5] Berlin L, Hall FM. More Mammography Muddle: Emotions, Politics, Science, Costs, and Polarization. Radiology 2010;255(2):311–6. [6] Nelson R. Mammography Guidelines Generate Confusion and Debate. American Journal of Nursing 2010;110(3):14–5. [7] Berry DA. Breast Cancer Screening: Controversy Of Impact. Breast 2013;22(Suppl 2(0 2)). (Edinburgh, Scotland). [S73-S6]. [8] E. Schattner, Getting The Math On Mammograms. Medical Lessons, November 20, 2009. Available from: http://www.medicallessons.net/2009/11/getting-the-mathon-mammograms/. [9] E. Schattner, Mammography: A Not-So-Fatalistic View, Huffington Post, November 23, 2009. Available from: https://www.huffpost.com/entry/mammography-a-notso-fata_b_367862. [10] Welch HG. Screening Mammography — A Long Run For A Short Slide? New England Journal of Medicine 2010;363:1276–8. [11] Elmore JG, Fletcher SW. Overdiagnosis In Breast Cancer Screening: Time To Tackle An Underappreciated Harm. Ann Intern Med 2012;156(7):536–7. [12] Kalager M, Adami H, Bretthauer M, Tamimi RM. Overdiagnosis Of Invasive Breast Cancer Due To Mammography Screening: Results From The Norwegian Screening Program. Ann Intern Med 2012;156(7):491–9. [13] Moyer VA. What We Don't Know Can Hurt Our Patients: Physician Innumeracy And Overuse Of Screening Tests. Ann Intern Med 2012;156(5):392–3. [14] Baum M. Harms From Breast Cancer Screening Outweigh Benefits If Death Caused By Treatment Is Included. BMJ 2013;346:f385. [15] Brodersen J, Siersma VD. Long-term Psychosocial Consequences Of False-Positive Screening Mammography. Ann Fam Med 2013;11(2):106–15. [16] Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty Five Year Follow-up For Breast Cancer Incidence And Mortality Of The Canadian National Breast Screening Study: Randomised Screening Trial. BMJ 2014;348:g366. [17] Welch HG, Passow HJ. Quantifying The Benefits And Harms Of Screening Mammography. JAMA Intern Med 2014;174(3):448–54. [18] R.C. Rabin, New Guidelines On Breast Cancer Draw Opposition, The New York Times, November 17, 2009. [19] G. Kolata, Mammograms’ Value In Cancer Fight At Issue, The New York Times, September 22, 2010. [20] N.C. Aizenman, Mammograms Leading To Unnecessary Treatment, Study Finds, Washington Post, November 21, 2012. [21] Mulcahy N. Study: 1.3 Million Overdiagnosed Breast Cancers In 30 Years. Medscape. November 21, 2012 Available from http://www.medscape.com/ viewarticle/774966. [22] M. Wadman, Benefits Of Mammograms Under Fire, Nature, November 21, 2012, Available from: doi:10.1038/nature.2012.11866. [23] P. Orenstein, Our Feel-Good War On Breast Cancer, New York Times Magazine, April 25, 2013. [24] Beck M. More Doubts About Mammograms' Value Are Raised In Large Study. Wall Street Journal April 1, 2014. [25] E. Schattner, A Turning Point In The Breast Cancer Screening Debate, Forbes, January 12, 2016. Available from: https://www.forbes.com/sites/elaineschattner/ 2016/01/12/a-turning-point-in-the-breast-cancer-screening-debate/. [26] E. Schattner, The Cases Against The Case Against Mammography, Forbes, October 13, 2016. Available from: https://www.forbes.com/sites/elaineschattner/2016/ 10/13/the-case-against-the-case-against-mammography-and-modern-breastcancer-screening/. [27] C. McIntyre, Is The Anti-Mammography Movement Based On Bad Science? Macleans Ca, May 26, 2017. Available from: https://www.macleans.ca/society/isthe-anti-mammography-movement-based-on-bad-science/. [28] Schattner E. Can Cancer Truths Be Told? Challenges For Medical Journalism American Society of Clinical Oncology Educational Book. 37. American Society of Clinical Oncology; 2017. p. 3–11. [29] Jin J. Breast Cancer Screening: Benefits And Harms. JAMA 2014;312(23):2585. [30] Healthwise. Breast Cancer Screening: When Should I Start Having Mammograms? Kaiser Permanente Available from: https://healthy.kaiserpermanente.org/healthwellness/health-encyclopedia/he.breast-cancer-screening-when-should-i-starthaving-mammograms.abh0460. [31] Breast Screening Decisions: A Mammogram Decision Aid For Women Ages 40–49. Weill Cornell Medicine. Available from: https://bsd.weill.cornell.edu/#/. [32] Keating NL, Pace L. Decisions, Decisions. Harvard Medical School News; 2018 Available from: https://hms.harvard.edu/news/decisions-decisions-0. [33] Masson V. Why I Don't Get Mammograms. Health Aff 2010;29(10):1958–60. [34] M.M.-O. Lee, Why I Never Got a Mammogram. The New York Times, February 14, 2014. [35] Aschwanden C. Why I'm Opting Out Of Mammography. JAMA Intern Med
6. Collaboration for women's health Reversing damage from the anti-mammography campaign will take years and effort. In preparing this article, I scanned Twitter for antiscreening posts and was repeatedly stung by the depth of unsupportable statements—shared alike by doctors and patient advocates—and dissonance in my feeds. As with politics, rifts are extreme. What's needed is productive and respectful dialogue among women's health, public health, radiology, pathology, epidemiology and oncology experts. Joint conferences and research would help. Worth demonstrating would be longer overall survival, and not just diseasespecific survival, in women who've been regularly screened. That information would put to rest concerns about overdiagnosis and overtreatment leading to harms, such as accelerated heart disease from radiation, chemotherapy or estrogen deprivation. A frequent complaint about mammography is that cancer prevention would be better than early detection. I couldn't agree more! However, research into breast cancer's causes is woefully lacking. A genetic disposition accounts for only 5–10% of cases [107,108]. While women can lower the likelihood of developing cancer by not smoking, keeping fit, and avoiding excessive alcohol consumption, lifestyle measures are not full-proof: Most breast cancers occur by chance [99]. Until scientists establish the causes, that it might be prevented, and policy-makers and the public accept those future findings and implement changes to reduce breast cancer's occurrence, early detection and adjuvant treatment are the only ways of reducing metastatic, lethal cases. When I first wrote about mammography in 2009, I weighed the expense of a large prospective trial as unjustifiable. I reasoned that because breast cancer can recur after many years, a meaningful study requires decades; as technology constantly advances, results from a trial, 15 years ahead, would not be useful. In retrospect, I underestimated naysayers' influence. Given how far down the screening story has gone in ten years, it's worth considering a large prospective clinical study—starting at age 35, given the rising prevalence and deaths in younger women from this disease—if that's what it takes to convince physician‑leaders and policy-makers. I have always maintained that screening is a choice; no woman should be pressured to get a mammogram. But doctors should be clear in the recommendation. Until prevention is feasible, I hope skeptics will at least remain open to the old-school possibility that finding and treating breast cancer early is the best way to lower premature deaths and suffering from metastatic disease.
2
4
All websites accessed on April 5, 2019, by the author.
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner 2015;175(2):164–5. [36] Jaggar K. Stop Routine Breast-Cancer Screenings. Science Has Shown They Don't Save Lives Washington Post May 5, 2015. [37] Dederich L. A Widely Used Guideline Said I Didn't Need A Mammogram. It Was Wrong, StatNews. October 12, 2018 Available from: https://www.statnews.com/ 2018/10/12/breast-cancer-screening-guidelines-wrong/. [38] Mammography Use. National Center for Health Statistics, U.S. Centers for Disease Control; 2017 Available from: https://www.cdc.gov/nchs/fastats/mammography. htm. [39] Jenkins M, Merker L, Gallegos N. Changes In Tumour Diameter Since The Introduction Of Breast Cancer Screening: An Observational Study From The SEER Database Between 1983–2014. (Plenary Abstract, European Breast Cancer Conference, Barcelona, March 2018). Eur J Cancer 2018;92:S12. [40] Siu AL. On Behalf Of The USPSTF. Screening For Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med 2016;164(4):279–96. [41] Procedure Manual. U.S. Preventive Services Task Force; Available from: https:// www.uspreventiveservicestaskforce.org/Page/Name/procedure-manual. [42] Kopans D. Arguments Against Mammography Screening Continue To Be Based On Faulty Science. Oncologist 2014;19(2):107–12. [43] Schattner E. A Call For Clarity On Mammography's Benefits And The Value Of Early Detection, Huffington Post. January 2, 2014 Available from: https://www. huffpost.com/entry/mammography_b_4523834. [44] Kopans DB. Mammograms Save Lives. Wall Street Journal May 22, 2014. [45] Schattner E. Why Women Shouldn't Cower To Concerns About Overdiagnosis Of Breast Cancer, Forbes. July 9, 2015 Available from: https://www.forbes.com/sites/ elaineschattner/2015/07/09/why-women-shouldnt-cower-to-concern-aboutbreast-cancer-overdiagnosis-by-mammography-jama-news/. [46] Schattner E. Recent Studies Of Mammography Use Shockingly Old Data, Forbes. March 16, 2015 Available from: https://www.forbes.com/sites/elaineschattner/ 2015/03/16/recent-studies-of-mammography-use-shockingly-old-data/. [47] Gøtzsche PC, Jørgensen KJ. Screening For Breast Cancer With Mammography. Cochrane Database Syst Rev 2013;6. [48] Pace LE, Keating NL. A Systematic Assessment Of Benefits And Risks To Guide Breast Cancer Screening Decisions. JAMA 2014;311(13):1327–35. [49] Nelson HD, Pappas M, Cantor A, Griffin J, Daeges M, Humphrey L. Harms Of Breast Cancer Screening: Systematic Review To Update The 2009 U.S. Preventive Services Task Force Recommendation. Ann Intern Med 2016;164(4):256–67. [50] Keating NL, Pace LE. Breast Cancer Screening In 2018: Time For Shared Decision Making. JAMA 2018;319(17):1814–5. [51] Bleyer A, Welch HG. Effect Of Three Decades Of Screening Mammography On Breast-Cancer Incidence. New England Journal of Medicine 2012;367(21):1998–2005. [52] Welch HG, Gorski DH, Albertsen PC. Trends In Metastatic Breast And Prostate Cancer — Lessons In Cancer Dynamics. New England Journal of Medicine 2015;373(18):1685–7. [53] Welch HG, Prorok PC, O'Malley AJ, Kramer BS. Breast-Cancer Tumor Size, Overdiagnosis, And Mammography Screening Effectiveness. New England Journal of Medicine 2016;375(15):1438–47. [54] Surveillance, Epidemiology, And End Results (SEER) Program. Table 4.8 Cancer Of The Female Breast (Invasive). SEER Cancer Statistics Review (CSR) 1975–2015. National Cancer Institute, Rockville, Maryland. Available from: https://seer.cancer. gov/csr/1975_2015/browse_csr.php? [55] Schattner E. A Distinct Conclusion On The Benefit Of Breast Cancer Screening (electronic comment), Massachusetts Medical Society. October 29, 2015 Available from: https://www.nejm.org/doi/10.1056/NEJMp1510443?#article_comments. [56] Schattner E. The Unfortunate Reality Of A Rising Rate Of Breast Cancer, Forbes. October 21, 2016 Available from: https://www.forbes.com/sites/elaineschattner/ 2016/10/21/the-unfortunate-reality-of-a-rising-rate-of-breast-cancer/. [57] Helvie MA, Chang JT, Hendrick RE, Banerjee M. Reduction In Late-Stage Breast Cancer Incidence In The Mammography Era: Implications For Overdiagnosis Of Invasive Cancer. Cancer 2014;120(17):2649–56. [58] Welch HG, Black WC. Overdiagnosis In Cancer. JNCI: Journal of the National Cancer Institute 2010;102(9):605–13. [59] Welch HG. Cancer Survivor Or Victim Of Overdiagnosis?, The New York Times. November 21, 2012. [60] Harding C, Pompei F, Burmistrov D, Welch H, Abebe R, Wilson R. Breast Cancer Screening, Incidence, And Mortality Across Us Counties. JAMA Intern Med 2015;175(9):1483–9. [61] Schattner E. How To Avoid Overdiagnosis And Overtreatment Of Breast Cancer, Forbes. July 16, 2015 Available from: https://www.forbes.com/sites/ elaineschattner/2015/07/16/how-to-avoid-overdiagnosis-and-overtreatment-ofbreast-cancer-improve-mammography-screening-quality/. [62] Carey B. Prominent Cancer Researcher Resigns From Dartmouth Amid Plagiarism Charges, The New York Times. September 14, 2018. [63] Welch HG, Schwartz LM, Woloshin S. Overdiagnosed: Making People Sick In The Pursuit Of Health. Boston, Mass: Beacon Press; 2011. [64] Welch HG. Cancer Screens Are A Gamble, The New York Times. October 10, 2011. [65] Welch HG. When Screening Is Bad For A Woman's Health, Los Angeles Times. July 19, 2015. [66] McDougall J, Gilbert H, Welch MD. Some Cancers Regress On Their Own. YouTube. November 5 2015 Available from https://youtu.be/OkBmCn4UwXM. [67] Welch HG. Cancer Screening III-overdiagnosis. YouTube. June 12, 2014 Available from: https://youtu.be/4A_Y42L0dMc. [68] Welch HG, Fisher ES. Income And Cancer Overdiagnosis — When Too Much Care Is Harmful. N Engl J Med 2017;376(23):2208–9.
[69] Newman D. Screening Mammography For Reducing Deaths (And Specifically, Breast Cancer Deaths) No Benefit Found. theNNT.com; October 6, 2010 Available from http://www.thennt.com/nnt/screening-mammography-for-reducingdeaths/. [70] Prasad V, Lenzer J, Newman DH. Why Cancer Screening Has Never Been Shown To “Save Lives”—And What We Can Do About It. BMJ 2016;352:h6080. [71] Newman DH. Ignoring The Science On Mammograms, The New York Times. November 28, 2012. [72] Newman DH. Hippocrates' Shadow: Secrets From The House Of Medicine. New York, NY: Scribner; 2008. [73] Frakt A, Carroll AE. Can This Treatment Help Me? There's A Statistic For That, The New York Times. January 26, 2015. [74] Laupacis A, Sackett DL, Roberts RS. An Assessment Of Clinically Useful Measures Of The Consequences Of Treatment. New England Journal of Medicine 1988;318(26):1728–33. [75] Rojas R. Manhattan Doctor Is Sentenced To 2 Years In Prison For Sexually Abusing Patients, The New York Times. January 23,2017. [76] Enserink M. Evidence-Based Medicine Group In Turmoil After Expulsion Of Cofounder. Science September 16, 2018;361(6408):1173–4. https://doi.org/10. 1126/science.361.6408.1173. [77] Vesper I. Mass Resignation Guts Board Of Prestigious Cochrane Collaboration. Nature September 17, 2018. https://doi.org/10.1038/d41586-018-06727-0 Available from: https://www.nature.com/articles/d41586-018-06727-0. [78] PubMed Review (ES, February 8, 2019). U.S. National Library Of Medicine, National Institutes Of Health. [79] Gøtzsche PC. Mammography Screening: Truth, Lies And Controversy. London; New York: Radcliffe Pub; 2012. [80] Biller-Andorno N, Jüni P. Abolishing Mammography Screening Programs? A View From The Swiss Medical Board N Engl J Med 2014;370(21):1965–7. [81] Gøtzsche PC. Mammography Screening Is Harmful And Should Be Abandoned. J R Soc Med 2015;108(9):341–5. [82] Topol EJ. Time To End Routine Mammography. Medscape May 6, 2015 Available from https://www.medscape.com/viewarticle/844153. [83] Park A. It's Time To End Mammograms, Some Experts Say, TIME. December 6, 2017 Available from: http://time.com/5050978/mammogram-breast-cancer/. [84] International Agency for Research on Cancer (IARC). Breast Cancer Fact Sheet. WHO; 2018 Available from http://gco.iarc.fr/today/fact-sheets-cancers. [85] Breast Cancer Statistics. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, Based On November 2017 Submission Data (1999-2015): U.S. Department Of Health And Human Services, Centers For Disease Control And Prevention And National Cancer Institute. Available from: https:// www.cdc.gov/cancer/breast/statistics/ [86] Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA Cancer J Clin 2019;69(1):7–34. [87] C.E. DeSantis, R.L. Siegel, A.G. Sauer, K.D. Miller, S.A. Fedewa, K.I. Alcaraz, et al. Cancer Statistics For African Americans, 2016: Progress And Opportunities In Reducing Racial Disparities. CA Cancer J Clin. 2016; 66(4): 290–308. [88] Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer. gov) SEER*Stat Database: mortality-all COD, aggregated total U.S. (1969–2016) < Katrina/Rita Population Adjustment > , National Cancer Institute, DCCPS, Surveillance Research Program, released December 2018. Underlying mortality data provided by NCHS (www.cdc.gov/nchs). [89] Hendrick RE, Baker JA, Helvie MA. Breast Cancer Deaths Averted Over 3 Decades. Cancer February 11, 2019. https://doi.org/10.1002/cncr.31954. [90] Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation Of The Number Of Women Living With Metastatic Breast Cancer In The United States. Cancer Epidemiology and Prevention Biomarkers 2017;26(6):809–15. [91] S.K. Plevritis, D. Munoz, A.W. Kurian, et al. Association Of Screening And Treatment With Breast Cancer Mortality By Molecular Subtype In Us Women, 2000–2012. JAMA. 2018; 319(2): 154–64. [92] Tabár L, Dean PB, Chen TH-H, Yen AM-F, Chen SL-S, Fann JC-Y, et al. The Incidence Of Fatal Breast Cancer Measures The Increased Effectiveness Of Therapy In Women Participating In Mammography Screening. Cancer 2019;125(4):515–23. [93] ,H. Pan, R. Gray, J. Braybrooke, C. Davies, C. Taylor, P. McGale, et al. 20-year Risks Of Breast-Cancer Recurrence After Stopping Endocrine Therapy At 5 years. New England Journal of Medicine. 2017; 377 (19): 1836–46. [94] Saadatmand S, Bretveld R, Siesling S, Tilanus-Linthorst MMA. Influence Of Tumour Stage At Breast Cancer Detection On Survival In Modern Times: Population Based Study in 173,797 Patients. BMJ 2015;351:h4901. [95] Mariotto AB, Zou Z, Zhang F, Howlader N, Kurian AW, Etzioni R. Can We Use Survival Data From Cancer Registries To Learn About Disease Recurrence? The Case Of Breast Cancer Cancer Epidemiology and Prevention Biomarkers 2018;27(11):1332–41. (with supplementary Table 4). [96] Arleo EK, Monticciolo DL, Monsees B, McGinty G, Sickles EA. Persistent Untreated Screening-Detected Breast Cancer: An Argument Against Delaying Screening Or Increasing The Interval Between Screenings. J Am Coll Radiol 2017;14(7):863–7. [97] Welch HG. NEJM Screening Mammograms II, YouTube. October 13, 2016 Available from: https://youtu.be/IwoIBTJD1VQ. [98] Surveillance, Epidemiology, and End Results (SEER) Program. Table 4.7 Cancer Of The Female Breast (Invasive). SEER Cancer Statistics Review (CSR) 1975–2015 Available from: https://seer.cancer.gov/csr/1975_2015/results_single/sect_04_ table.07.pdf. [99] Breast Cancer Facts & Figures 2017–2018. Atlanta: American Cancer Society; 2017. [100] C.D. Lehman, R.F. Arao, B.L. Sprague, J.M. Lee, D.S.M. Buist, K. Kerlikowske, et al. National Performance Benchmarks For Modern Screening Digital Mammography:
5
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
[101]
[102] [103] [104]
Update From The Breast Cancer Surveillance Consortium. Radiology. 2017; 283(1): 49–58. E.F. Conant, W.E. Barlow, S.D. Herschorn, D.L. Weaver, E.F. Beaber, A.N.A. Tosteson, et al. Association Of Digital Breast Tomosynthesis vs Digital Mammography With Cancer Detection And Recall Rates By Age And Breast Density. JAMA Oncol. 2019 Feb 28. H.G. Welch, Opinion: Mammograms Can Help–And Harm - CNN, November 20, 2013, Available from: https://www.cnn.com/2013/11/20/opinion/welchmammogram-robach/index.html. Aschwanden C. The Case Against Early Cancer Detection. FiveThirtyEight November 24, 2014 Available from: https://fivethirtyeight.com/features/thecase-against-early-cancer-detection/. Gawande A. Overkill. The New Yorker; May 11, 2015.
[105] Knox R. With Cancer Diagnoses, Better-Off Americans May Get Too Much Attention, Commonhealth: WBUR. June 8, 2017. [106] Welch HG. Treatment. The Heterogeneity Of Cancer. Breast Cancer Res Treat 2018;169(2):207–8. [107] Valencia OM, Samuel SE, Viscusi RK, Riall TS, Neumayer LA, Aziz H. The Role Of Genetic Testing In Patients With Breast Cancer: A Review Role Of Genetic Testing In Patients With Breast Cancer Role Of Genetic Testing In Patients With Breast Cancer. JAMA Surg 2017;152(6):589–94. [108] CDC. Groups At Higher Risk For Hereditary Breast And Ovarian Cancer: Centers For Disease Control And Prevention Available from: https://www.cdc.gov/cancer/ breast/young_women/bringyourbrave/hereditary_breast_cancer/higher_risk_ cancer.htm.
6
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Breast Imaging
Correcting a decade of negative news about mammography Elaine Schattner Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College, New York, NY 10021, United States of America
1. Introduction It's been ten years since the U.S. Preventive Services Task Force (USPSTF) pulled back on recommendations for breast cancer screening of women ages 40–49 years [1]. When the controversy broke in November 2009 [2–4], I had recently completed a master's degree in journalism. The news hit close for two reasons: I'd practiced oncology and seen the devastating effects of advanced disease; and because a superb radiologist had detected a small invasive tumor in my left breast when I was age 42. After surgery and a short course of chemotherapy, my prognosis was excellent. I considered myself lucky! While debate intensified [5–7], I followed closely—with a mix of fascination and concern [8,9]. As a physician, I was disturbed by how frequently false assumptions about factual subjects—ranging from breast cancer's incidence to women's psychology—played into nominally objective analyses published in top-tier medical journals. A flood of damaging reports amplified perceived risk of “overdiagnosis” and overtreatment. Study after flawed study—like a house of cards—touted mammography's alleged harms and costs [10–17]. “Mammography does more harm than good” sums up countless headlines. The revelation of mammography's imperfectness—the story of it having been oversold—drew readers and angry comments [18–24]. For a while, I was stunned by the volume of negative hype, and by some health editors' apparent exuberance over downbeat conclusions. As journalism was shifting from print to predominantly digital media, I wondered if the truth about modern screening, however complicated, mattered less than providing a counternarrative [25–28]. Women and primary care doctors are plenty aware of mammography's limits. A decade's worth of negative analyses and neat decision tools, based on archaic data [29–32], have persuaded many women to avoid, delay or deliberately skip getting screened [33–37]. In 2015, only 64% of U.S. women over age 40 reported having a mammogram within two years [38]. Since 2010, the proportion screened has been falling. After dropping and stabilizing, the average diameter of newlydiagnosed breast cancers has crept back above 2 cm [39]. Now I'm worried. In 2019, many doctors, journalists and advocates consider the matter settled—against mammography, particularly for women ages 40 - 49 years. Soon the USPSTF will again start updating its recommendations. The Task Force last published breast cancer screening guidelines in
January 2016 [40]. The multistep process, including public comments on the draft, takes over a year [41]. The next USPSTF review presents an opportunity to correct misinformation. Women deserve fair guidance about screening's risks and benefits. For this reason, the Agency for Healthcare Research and Quality (AHRQ), which controls USPSTF membership, should appoint doctors who are most knowledgeable about mammography, including radiologists, to the government panel along with primary care physicians, epidemiologists and public health experts. While concerns may arise about specialists' potential conflicts of interest, radiologists' knowledge is necessary to assure the panel is reasonably familiar with current technology and screening facts. Other experts who should participate include pathologists, surgeons, breast oncologists and patient advocates, because they have the most experience with breast cancer diagnosis, treatment and survivorship. 2. Problematic literature Errors cloud the literature on mammography [26,27,42–45]. Previously I've reported on the problematic reliance of seemingly recent studies on screens using outdated equipment [46]. For instance, the 2013 Cochrane review includes results from the 1960s [47]. An oftcited Canadian study examined outcomes after mammograms taken in five consecutive years during the mid-1980s [16]. Perhaps the dates wouldn't matter if mammography were a straightforward measure, like checking a sodium level or hemoglobin. But imaging technology has advanced! Consider how cell phones and cameras have improved since 1985. Would you choose a device today based on a 1990 summary? Of course not! Yet investigators continue plugging old findings into fresh reports and decision aides [48–50]. Incorrect assumptions undermine conclusions from observational studies. Among the most egregious mistakes is the constant underlying disease burden assumed by Welch and colleagues [51]. After noting that metastatic breast cancer rates did not drop in the mammography era, they infer that screening must be ineffective [51–54]. However, Welch and colleagues fail to account for the increasing baseline rate of disease: from 1975 to 2015, the overall incidence of invasive breast cancers rose by approximately 25% among U.S. women [54]. Given this upward trend, an alternative conclusion can be drawn: Without mammography, advanced tumors would be more frequent [55,56]. Other
E-mail addresses: [email protected], [email protected]. https://doi.org/10.1016/j.clinimag.2019.03.011 Received 15 January 2019; Received in revised form 7 March 2019; Accepted 25 March 2019 0899-7071/ © 2019 Published by Elsevier Inc.
Please cite this article as: Elaine Schattner, Clinical Imaging, https://doi.org/10.1016/j.clinimag.2019.03.011
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
investigators, by adjusting for changes in the underlying disease rate, have found a relative reduction in metastatic cases [57]. In general, the anti-screening literature ignores 30 years of progress in radiology and pathology. “Overdiagnosis” cannot be directly measured. Many reports conflate overdiagnosis—a concept—and overtreatment [17,58–60], which indeed causes harm and can be prevented by educating doctors and patients, so they don't overreact to small tumors [61]. Other problems include crossover effects between study arms of randomized trials. Physicians and economists have, so far, failed to weigh and report on the consequences of delayed breast cancer diagnosis [45,61].
Temporal trends in U.S. breast cancer mortality, women ages 40+, 1969-2016 80
1989 Rate, 74.0 per 100,000 Women
70 -40%
60 50 2016 Rate, 44.6 per 100,000 Women
40 30
3. Concerning sources
20
It is troubling that so many high-profile papers were authored by a few individuals. Dr. H. Gilbert Welch, a family physician who was a professor at Dartmouth, resigned in 2018 after the university determined that he had committed plagiarism [62]. Welch wrote a popular book and numerous op-ed pieces about overdiagnosis [59,63–65]. Journalists quoted him. In talks and YouTube videos, Welch promoted theories that as many as 1 in 5 breast cancers can regress without treatment [66,67]. He suggested that breast cancer is a disease of affluence [68]. If someone commits plagiarism their conclusions may still be true. The same goes for a criminal physician such as Dr. David Newman, an emergency room doctor, former professor, and screening opponent [69,70]. Newman impressed leadership of the Association of Health Care Journalists and argued against mammography in The New York Times [71]. His book, Hippocrates' Shadow, was printed in multiple editions and translated [72]. He founded theNNT.com website—a “clearinghouse” [73] for data on the Number Needed to Treat [74], a statistical tool to inform medical decisions. TheNNT.com summary on screening mammography states: “None were helped.” Until 2016, he was active on social media, but his accounts have been removed.1 In 2017, he was sentenced to jail for sexually assaulting female patients [75]. Another influential anti-mammographer, Dr. Peter Gøtzsche, was recently expelled from the Cochrane Collaboration [76,77], a prestigious organization that reviews medical evidence. The uproar had to do with his concerns about human papillomavirus vaccination. Over two decades, Gøtzsche published over eighty papers on screening [78]. His book, Mammography Screening: Truth, Lies and Controversy, contains a forward by the president of the National Breast Cancer Coalition; she reflects on when Gøtzsche spoke before a large audience of patient advocates [79]. He is first author of the 2013 Cochrane review which assumes “overdiagnosis and overtreatment is at 30%” and harps on women's psychological distress from screening [47]. Each of these individuals has had an immeasurable sway on how people view mammography. Perhaps the greater point is that everyone should be skeptical of all information and sources, including reports in major medical journals and books.
10 0 1969
1979
1989
1999
2009
2019
Fig. 1. Age-adjusted U.S. Breast Cancer Mortality Rates, Women Ages 40+, 1969–2016 (graph courtesy R. E. Hendrick, Ph.D.); Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality - All COD, Aggregated Total U.S. (1969–2016) < Katrina/Rita Population Adjustment > , National Cancer Institute, DCCPS, Surveillance Research Program, released December 2018. Underlying mortality data provided by NCHS (www.cdc.gov/nchs).
I believe that breast cancer is an urgent public health concern. This disease remains a leading killer of middle-aged women. Rates are increasing globally, including in poor countries [84]. In the United States, breast cancer is one of few malignancies with increasing incidence [85,86]. The rise is particularly steep among African American women [87]. Tragically, many patients present with advanced disease that might have been found at earlier stage: The concept of “underdiagnosis” should be considered. Abandoning mammography now—with the disease rate on the up—would be catastrophic to women's health. Rather, physicians and advocates need be informed of current evidence supporting screening's clinical benefit. The most powerful data are correlative: From 1989 to 2016—coincident with widespread uptake of mammography—mortality from breast cancer fell by 40% in the United States [86]. Among women over age 40 years, the death rate stayed constant from the late 1960s until 1989, when it began a steady decline (Fig. 1) [88,89]. This progress occurred despite a rising incidence of invasive cases [86]. Treatment advances cannot simply account for such a steep drop in the death rate, because metastatic disease remains incurable [90]. Rather, screening plays a significant role. In 2018, the NCI's Cancer Intervention and Surveillance Network (CISNET) confirmed that screening, combined with adjuvant therapy, is a major contributor to reducing breast cancer mortality in modern times. Using six distinct models developed at separate institutions, for 2012 the CISNET group attributed 37% of the lowering of deaths to screening. Of note, they found that screening confers a comparatively large reduction in mortality from aggressive breast cancer forms, such as Her2 positive and triple negative disease [91]. Most recently, an international group of researchers probed six decades of Swedish population registry data for fatal breast cancers. They observed a profound and durable reduction in breast cancer deaths among women who participated in mammography programs. In the first ten years after diagnosis, the risk of dying from breast cancer was 60% lower among screened than unscreened women; within 20 years after diagnosis, the risk was 47% lower [92]. These observations are not anecdotes (“a mammogram saved my life”), but statistically strong, population-based findings that support screening. Amid progress in molecular diagnostics and targeted therapy for breast cancer, clinical stage at diagnosis still holds a profound influence
4. Clarifying the picture Today, the anti-mammography campaign has so much traction that women's access to screening may be jeopardized. Influential physicians have proposed that routine mammography be stopped [80–83]. Since my diagnosis in 2002, a generation of young doctors has been educated in screening's harms, but without memory of an earlier era—when most breast cancer patients presented with palpable masses and later-stage disease. 1 Dr. Newman's influence is hard to gauge because his social media accounts have been removed; articles about his work appear to have been scrubbed from websites including journalistic outlets.
2
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
Long-term Outcomes Aer Estrogen Receptor Posive Breast Cancer
Fig. 2. A. Risk of distant recurrence (left) or death from breast cancer (right) 5, 10, 15 and 20 years after diagnosis, among 74,194 women with T1 or T2 Estrogen Receptor-positive disease scheduled to receive 5 years of endocrine therapy in a clinical trial, by pathological lymph node status. (Data source: N Engl J Med 2017; 377: 1836–46, Fig. 2.) B. Risk of distant recurrence 10, 15 and 20 years after diagnosis among 62,923 women with T1 (left) or T2 (right) breast cancer who initiated endocrine therapy within 5 years of enrolling in a clinical trial. (Data source: N Engl J Med 2017; 377: 1836–46, Fig. 3.)
on long-term outcomes. A 2017 report detailed recurrences and deaths among over 60,000 women with the most common form of breast cancer: estrogen-receptor (ER) positive (+) disease [93]. These investigators aimed to discern trends after endocrine therapy for earlystage (T1, ≤2 cm; and T2, 2–5 cm) disease; they did not intend to study screening. Nonetheless, a striking pattern emerged from this large analysis (Fig. 2). Twenty years after early-stage breast cancer, cumulative risk of distant (metastatic) recurrence ranged from 13%, after small node-negative cases, to 41% after tumors of 2–5 cm with 4–9 positive lymph nodes. For stage 3 breast cancer, not included in this paper, recurrence and death rates are even higher [94,95]. These findings indicate that the likelihood of recurrence or death from breast cancer is critically dependent on initial tumor stage: the smaller the better; the fewer lymph nodes involved, the better. As things stand, screening is the only way to detect breast cancer before it's so large that a woman or doctor might palpate the mass.
[97], particularly in elderly patients who are more likely to die from something else, the suggestion that it's preferable for a healthy woman to let breast cancer go unchecked until it's large enough that she feels a lump or experiences symptoms is foolish. A bitter source of misunderstanding is the fact that over 42,000 Americans will die from breast cancer this year [86]. Although diseasespecific mortality has fallen, the absolute number of deaths from breast cancer has been constant. This disconnect stems from the climbing baseline rate of invasive breast cancer—from 102 to 133 cases, in 1975 and 2015 respectively, per 100,000 adults [98]—in an expanding U.S. population. Causes of the rising incidence of breast cancer include aging, obesity and other factors warranting research [99]. While mammography is not foolproof, it's far better than some readers may be aware. In specialized radiology practices the pick-up rate (sensitivity) of mammography is around 85% [100]. With addition of breast ultrasound and other tools including MRI, screening's sensitivity surpasses 90%. Digital tomosynthesis, popularly known as 3D mammography, will further improve screening's accuracy [101], along with artificial intelligence. A pet peeve is the likening of breast tumors to barnyard animals such as birds, rabbits and turtles. These similes appear in news [102,103], magazine stories [104], radio [105], and YouTube videos
5. Correcting myths There is no evidence that breast cancer can vanish without treatment [96]. While slow-growing tumors don't necessarily cause harm 3
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
References2
[67,97]. If I were in the office of a physician who explained that I shouldn't get a mammogram because lethal tumors are like birds, which can't be caught, and turtle-type tumors are unlikely to kill me, I'd exit quickly. The barnyard pen theory of cancer and its capturability [106] has no relationship to actual pathology or medical science. The fact is, indolent tumors can be lethal. And most breast cancers, including faster-growing types, can be detected by mammography. A popular and divisive falsehood—widely shared on social media—is that “30%” of early-stage breast cancers recur after treatment. However, there is no modern evidence to support this statistic. Years ago, such as in the 1960s and 1970s, before screening and routine prescription of adjuvant therapy, recurrence rates were indeed higher. In 2018, a group of biostatisticians reported that in recent decades, 20% of early-stage patients, overall, experience recurrence within 20 years of diagnosis [95]. While worrying about late recurrence of hormonesensitive breast cancer is understandable, women would be wise to know that stage 1 tumors are less likely to recur than stage 3, and that most tumors—80%—don't come back [95]. Some doctors suggest that as treatments for breast cancer advance, the benefits of mammography diminish. But perhaps the opposite is true: If there were no effective remedies for early-stage disease, screening would be pointless.
[1] USPSTF. Screening For Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med 2009;151(10):716–26. [2] G. Kolata, Panel Urges Mammograms At 50, Not 40, The New York Times, November 16, 2009. [3] R. Siegel and M. Block, On Mammogram Recommendation, An Intense Debate, In: All Things Considered, NPR, November 19, 2009. [4] Cohen E. I Want My Mammograms!. CNN; November 19, 2009 Available from: http://web.archive.org/web/20181216061312/http://www.cnn.com/2009/ HEALTH/11/19/mammogram.guidelines.insurance/index.html. [5] Berlin L, Hall FM. More Mammography Muddle: Emotions, Politics, Science, Costs, and Polarization. Radiology 2010;255(2):311–6. [6] Nelson R. Mammography Guidelines Generate Confusion and Debate. American Journal of Nursing 2010;110(3):14–5. [7] Berry DA. Breast Cancer Screening: Controversy Of Impact. Breast 2013;22(Suppl 2(0 2)). (Edinburgh, Scotland). [S73-S6]. [8] E. Schattner, Getting The Math On Mammograms. Medical Lessons, November 20, 2009. Available from: http://www.medicallessons.net/2009/11/getting-the-mathon-mammograms/. [9] E. Schattner, Mammography: A Not-So-Fatalistic View, Huffington Post, November 23, 2009. Available from: https://www.huffpost.com/entry/mammography-a-notso-fata_b_367862. [10] Welch HG. Screening Mammography — A Long Run For A Short Slide? New England Journal of Medicine 2010;363:1276–8. [11] Elmore JG, Fletcher SW. Overdiagnosis In Breast Cancer Screening: Time To Tackle An Underappreciated Harm. Ann Intern Med 2012;156(7):536–7. [12] Kalager M, Adami H, Bretthauer M, Tamimi RM. Overdiagnosis Of Invasive Breast Cancer Due To Mammography Screening: Results From The Norwegian Screening Program. Ann Intern Med 2012;156(7):491–9. [13] Moyer VA. What We Don't Know Can Hurt Our Patients: Physician Innumeracy And Overuse Of Screening Tests. Ann Intern Med 2012;156(5):392–3. [14] Baum M. Harms From Breast Cancer Screening Outweigh Benefits If Death Caused By Treatment Is Included. BMJ 2013;346:f385. [15] Brodersen J, Siersma VD. Long-term Psychosocial Consequences Of False-Positive Screening Mammography. Ann Fam Med 2013;11(2):106–15. [16] Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty Five Year Follow-up For Breast Cancer Incidence And Mortality Of The Canadian National Breast Screening Study: Randomised Screening Trial. BMJ 2014;348:g366. [17] Welch HG, Passow HJ. Quantifying The Benefits And Harms Of Screening Mammography. JAMA Intern Med 2014;174(3):448–54. [18] R.C. Rabin, New Guidelines On Breast Cancer Draw Opposition, The New York Times, November 17, 2009. [19] G. Kolata, Mammograms’ Value In Cancer Fight At Issue, The New York Times, September 22, 2010. [20] N.C. Aizenman, Mammograms Leading To Unnecessary Treatment, Study Finds, Washington Post, November 21, 2012. [21] Mulcahy N. Study: 1.3 Million Overdiagnosed Breast Cancers In 30 Years. Medscape. November 21, 2012 Available from http://www.medscape.com/ viewarticle/774966. [22] M. Wadman, Benefits Of Mammograms Under Fire, Nature, November 21, 2012, Available from: doi:10.1038/nature.2012.11866. [23] P. Orenstein, Our Feel-Good War On Breast Cancer, New York Times Magazine, April 25, 2013. [24] Beck M. More Doubts About Mammograms' Value Are Raised In Large Study. Wall Street Journal April 1, 2014. [25] E. Schattner, A Turning Point In The Breast Cancer Screening Debate, Forbes, January 12, 2016. Available from: https://www.forbes.com/sites/elaineschattner/ 2016/01/12/a-turning-point-in-the-breast-cancer-screening-debate/. [26] E. Schattner, The Cases Against The Case Against Mammography, Forbes, October 13, 2016. Available from: https://www.forbes.com/sites/elaineschattner/2016/ 10/13/the-case-against-the-case-against-mammography-and-modern-breastcancer-screening/. [27] C. McIntyre, Is The Anti-Mammography Movement Based On Bad Science? Macleans Ca, May 26, 2017. Available from: https://www.macleans.ca/society/isthe-anti-mammography-movement-based-on-bad-science/. [28] Schattner E. Can Cancer Truths Be Told? Challenges For Medical Journalism American Society of Clinical Oncology Educational Book. 37. American Society of Clinical Oncology; 2017. p. 3–11. [29] Jin J. Breast Cancer Screening: Benefits And Harms. JAMA 2014;312(23):2585. [30] Healthwise. Breast Cancer Screening: When Should I Start Having Mammograms? Kaiser Permanente Available from: https://healthy.kaiserpermanente.org/healthwellness/health-encyclopedia/he.breast-cancer-screening-when-should-i-starthaving-mammograms.abh0460. [31] Breast Screening Decisions: A Mammogram Decision Aid For Women Ages 40–49. Weill Cornell Medicine. Available from: https://bsd.weill.cornell.edu/#/. [32] Keating NL, Pace L. Decisions, Decisions. Harvard Medical School News; 2018 Available from: https://hms.harvard.edu/news/decisions-decisions-0. [33] Masson V. Why I Don't Get Mammograms. Health Aff 2010;29(10):1958–60. [34] M.M.-O. Lee, Why I Never Got a Mammogram. The New York Times, February 14, 2014. [35] Aschwanden C. Why I'm Opting Out Of Mammography. JAMA Intern Med
6. Collaboration for women's health Reversing damage from the anti-mammography campaign will take years and effort. In preparing this article, I scanned Twitter for antiscreening posts and was repeatedly stung by the depth of unsupportable statements—shared alike by doctors and patient advocates—and dissonance in my feeds. As with politics, rifts are extreme. What's needed is productive and respectful dialogue among women's health, public health, radiology, pathology, epidemiology and oncology experts. Joint conferences and research would help. Worth demonstrating would be longer overall survival, and not just diseasespecific survival, in women who've been regularly screened. That information would put to rest concerns about overdiagnosis and overtreatment leading to harms, such as accelerated heart disease from radiation, chemotherapy or estrogen deprivation. A frequent complaint about mammography is that cancer prevention would be better than early detection. I couldn't agree more! However, research into breast cancer's causes is woefully lacking. A genetic disposition accounts for only 5–10% of cases [107,108]. While women can lower the likelihood of developing cancer by not smoking, keeping fit, and avoiding excessive alcohol consumption, lifestyle measures are not full-proof: Most breast cancers occur by chance [99]. Until scientists establish the causes, that it might be prevented, and policy-makers and the public accept those future findings and implement changes to reduce breast cancer's occurrence, early detection and adjuvant treatment are the only ways of reducing metastatic, lethal cases. When I first wrote about mammography in 2009, I weighed the expense of a large prospective trial as unjustifiable. I reasoned that because breast cancer can recur after many years, a meaningful study requires decades; as technology constantly advances, results from a trial, 15 years ahead, would not be useful. In retrospect, I underestimated naysayers' influence. Given how far down the screening story has gone in ten years, it's worth considering a large prospective clinical study—starting at age 35, given the rising prevalence and deaths in younger women from this disease—if that's what it takes to convince physician‑leaders and policy-makers. I have always maintained that screening is a choice; no woman should be pressured to get a mammogram. But doctors should be clear in the recommendation. Until prevention is feasible, I hope skeptics will at least remain open to the old-school possibility that finding and treating breast cancer early is the best way to lower premature deaths and suffering from metastatic disease.
2
4
All websites accessed on April 5, 2019, by the author.
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner 2015;175(2):164–5. [36] Jaggar K. Stop Routine Breast-Cancer Screenings. Science Has Shown They Don't Save Lives Washington Post May 5, 2015. [37] Dederich L. A Widely Used Guideline Said I Didn't Need A Mammogram. It Was Wrong, StatNews. October 12, 2018 Available from: https://www.statnews.com/ 2018/10/12/breast-cancer-screening-guidelines-wrong/. [38] Mammography Use. National Center for Health Statistics, U.S. Centers for Disease Control; 2017 Available from: https://www.cdc.gov/nchs/fastats/mammography. htm. [39] Jenkins M, Merker L, Gallegos N. Changes In Tumour Diameter Since The Introduction Of Breast Cancer Screening: An Observational Study From The SEER Database Between 1983–2014. (Plenary Abstract, European Breast Cancer Conference, Barcelona, March 2018). Eur J Cancer 2018;92:S12. [40] Siu AL. On Behalf Of The USPSTF. Screening For Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med 2016;164(4):279–96. [41] Procedure Manual. U.S. Preventive Services Task Force; Available from: https:// www.uspreventiveservicestaskforce.org/Page/Name/procedure-manual. [42] Kopans D. Arguments Against Mammography Screening Continue To Be Based On Faulty Science. Oncologist 2014;19(2):107–12. [43] Schattner E. A Call For Clarity On Mammography's Benefits And The Value Of Early Detection, Huffington Post. January 2, 2014 Available from: https://www. huffpost.com/entry/mammography_b_4523834. [44] Kopans DB. Mammograms Save Lives. Wall Street Journal May 22, 2014. [45] Schattner E. Why Women Shouldn't Cower To Concerns About Overdiagnosis Of Breast Cancer, Forbes. July 9, 2015 Available from: https://www.forbes.com/sites/ elaineschattner/2015/07/09/why-women-shouldnt-cower-to-concern-aboutbreast-cancer-overdiagnosis-by-mammography-jama-news/. [46] Schattner E. Recent Studies Of Mammography Use Shockingly Old Data, Forbes. March 16, 2015 Available from: https://www.forbes.com/sites/elaineschattner/ 2015/03/16/recent-studies-of-mammography-use-shockingly-old-data/. [47] Gøtzsche PC, Jørgensen KJ. Screening For Breast Cancer With Mammography. Cochrane Database Syst Rev 2013;6. [48] Pace LE, Keating NL. A Systematic Assessment Of Benefits And Risks To Guide Breast Cancer Screening Decisions. JAMA 2014;311(13):1327–35. [49] Nelson HD, Pappas M, Cantor A, Griffin J, Daeges M, Humphrey L. Harms Of Breast Cancer Screening: Systematic Review To Update The 2009 U.S. Preventive Services Task Force Recommendation. Ann Intern Med 2016;164(4):256–67. [50] Keating NL, Pace LE. Breast Cancer Screening In 2018: Time For Shared Decision Making. JAMA 2018;319(17):1814–5. [51] Bleyer A, Welch HG. Effect Of Three Decades Of Screening Mammography On Breast-Cancer Incidence. New England Journal of Medicine 2012;367(21):1998–2005. [52] Welch HG, Gorski DH, Albertsen PC. Trends In Metastatic Breast And Prostate Cancer — Lessons In Cancer Dynamics. New England Journal of Medicine 2015;373(18):1685–7. [53] Welch HG, Prorok PC, O'Malley AJ, Kramer BS. Breast-Cancer Tumor Size, Overdiagnosis, And Mammography Screening Effectiveness. New England Journal of Medicine 2016;375(15):1438–47. [54] Surveillance, Epidemiology, And End Results (SEER) Program. Table 4.8 Cancer Of The Female Breast (Invasive). SEER Cancer Statistics Review (CSR) 1975–2015. National Cancer Institute, Rockville, Maryland. Available from: https://seer.cancer. gov/csr/1975_2015/browse_csr.php? [55] Schattner E. A Distinct Conclusion On The Benefit Of Breast Cancer Screening (electronic comment), Massachusetts Medical Society. October 29, 2015 Available from: https://www.nejm.org/doi/10.1056/NEJMp1510443?#article_comments. [56] Schattner E. The Unfortunate Reality Of A Rising Rate Of Breast Cancer, Forbes. October 21, 2016 Available from: https://www.forbes.com/sites/elaineschattner/ 2016/10/21/the-unfortunate-reality-of-a-rising-rate-of-breast-cancer/. [57] Helvie MA, Chang JT, Hendrick RE, Banerjee M. Reduction In Late-Stage Breast Cancer Incidence In The Mammography Era: Implications For Overdiagnosis Of Invasive Cancer. Cancer 2014;120(17):2649–56. [58] Welch HG, Black WC. Overdiagnosis In Cancer. JNCI: Journal of the National Cancer Institute 2010;102(9):605–13. [59] Welch HG. Cancer Survivor Or Victim Of Overdiagnosis?, The New York Times. November 21, 2012. [60] Harding C, Pompei F, Burmistrov D, Welch H, Abebe R, Wilson R. Breast Cancer Screening, Incidence, And Mortality Across Us Counties. JAMA Intern Med 2015;175(9):1483–9. [61] Schattner E. How To Avoid Overdiagnosis And Overtreatment Of Breast Cancer, Forbes. July 16, 2015 Available from: https://www.forbes.com/sites/ elaineschattner/2015/07/16/how-to-avoid-overdiagnosis-and-overtreatment-ofbreast-cancer-improve-mammography-screening-quality/. [62] Carey B. Prominent Cancer Researcher Resigns From Dartmouth Amid Plagiarism Charges, The New York Times. September 14, 2018. [63] Welch HG, Schwartz LM, Woloshin S. Overdiagnosed: Making People Sick In The Pursuit Of Health. Boston, Mass: Beacon Press; 2011. [64] Welch HG. Cancer Screens Are A Gamble, The New York Times. October 10, 2011. [65] Welch HG. When Screening Is Bad For A Woman's Health, Los Angeles Times. July 19, 2015. [66] McDougall J, Gilbert H, Welch MD. Some Cancers Regress On Their Own. YouTube. November 5 2015 Available from https://youtu.be/OkBmCn4UwXM. [67] Welch HG. Cancer Screening III-overdiagnosis. YouTube. June 12, 2014 Available from: https://youtu.be/4A_Y42L0dMc. [68] Welch HG, Fisher ES. Income And Cancer Overdiagnosis — When Too Much Care Is Harmful. N Engl J Med 2017;376(23):2208–9.
[69] Newman D. Screening Mammography For Reducing Deaths (And Specifically, Breast Cancer Deaths) No Benefit Found. theNNT.com; October 6, 2010 Available from http://www.thennt.com/nnt/screening-mammography-for-reducingdeaths/. [70] Prasad V, Lenzer J, Newman DH. Why Cancer Screening Has Never Been Shown To “Save Lives”—And What We Can Do About It. BMJ 2016;352:h6080. [71] Newman DH. Ignoring The Science On Mammograms, The New York Times. November 28, 2012. [72] Newman DH. Hippocrates' Shadow: Secrets From The House Of Medicine. New York, NY: Scribner; 2008. [73] Frakt A, Carroll AE. Can This Treatment Help Me? There's A Statistic For That, The New York Times. January 26, 2015. [74] Laupacis A, Sackett DL, Roberts RS. An Assessment Of Clinically Useful Measures Of The Consequences Of Treatment. New England Journal of Medicine 1988;318(26):1728–33. [75] Rojas R. Manhattan Doctor Is Sentenced To 2 Years In Prison For Sexually Abusing Patients, The New York Times. January 23,2017. [76] Enserink M. Evidence-Based Medicine Group In Turmoil After Expulsion Of Cofounder. Science September 16, 2018;361(6408):1173–4. https://doi.org/10. 1126/science.361.6408.1173. [77] Vesper I. Mass Resignation Guts Board Of Prestigious Cochrane Collaboration. Nature September 17, 2018. https://doi.org/10.1038/d41586-018-06727-0 Available from: https://www.nature.com/articles/d41586-018-06727-0. [78] PubMed Review (ES, February 8, 2019). U.S. National Library Of Medicine, National Institutes Of Health. [79] Gøtzsche PC. Mammography Screening: Truth, Lies And Controversy. London; New York: Radcliffe Pub; 2012. [80] Biller-Andorno N, Jüni P. Abolishing Mammography Screening Programs? A View From The Swiss Medical Board N Engl J Med 2014;370(21):1965–7. [81] Gøtzsche PC. Mammography Screening Is Harmful And Should Be Abandoned. J R Soc Med 2015;108(9):341–5. [82] Topol EJ. Time To End Routine Mammography. Medscape May 6, 2015 Available from https://www.medscape.com/viewarticle/844153. [83] Park A. It's Time To End Mammograms, Some Experts Say, TIME. December 6, 2017 Available from: http://time.com/5050978/mammogram-breast-cancer/. [84] International Agency for Research on Cancer (IARC). Breast Cancer Fact Sheet. WHO; 2018 Available from http://gco.iarc.fr/today/fact-sheets-cancers. [85] Breast Cancer Statistics. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, Based On November 2017 Submission Data (1999-2015): U.S. Department Of Health And Human Services, Centers For Disease Control And Prevention And National Cancer Institute. Available from: https:// www.cdc.gov/cancer/breast/statistics/ [86] Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA Cancer J Clin 2019;69(1):7–34. [87] C.E. DeSantis, R.L. Siegel, A.G. Sauer, K.D. Miller, S.A. Fedewa, K.I. Alcaraz, et al. Cancer Statistics For African Americans, 2016: Progress And Opportunities In Reducing Racial Disparities. CA Cancer J Clin. 2016; 66(4): 290–308. [88] Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer. gov) SEER*Stat Database: mortality-all COD, aggregated total U.S. (1969–2016) < Katrina/Rita Population Adjustment > , National Cancer Institute, DCCPS, Surveillance Research Program, released December 2018. Underlying mortality data provided by NCHS (www.cdc.gov/nchs). [89] Hendrick RE, Baker JA, Helvie MA. Breast Cancer Deaths Averted Over 3 Decades. Cancer February 11, 2019. https://doi.org/10.1002/cncr.31954. [90] Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation Of The Number Of Women Living With Metastatic Breast Cancer In The United States. Cancer Epidemiology and Prevention Biomarkers 2017;26(6):809–15. [91] S.K. Plevritis, D. Munoz, A.W. Kurian, et al. Association Of Screening And Treatment With Breast Cancer Mortality By Molecular Subtype In Us Women, 2000–2012. JAMA. 2018; 319(2): 154–64. [92] Tabár L, Dean PB, Chen TH-H, Yen AM-F, Chen SL-S, Fann JC-Y, et al. The Incidence Of Fatal Breast Cancer Measures The Increased Effectiveness Of Therapy In Women Participating In Mammography Screening. Cancer 2019;125(4):515–23. [93] ,H. Pan, R. Gray, J. Braybrooke, C. Davies, C. Taylor, P. McGale, et al. 20-year Risks Of Breast-Cancer Recurrence After Stopping Endocrine Therapy At 5 years. New England Journal of Medicine. 2017; 377 (19): 1836–46. [94] Saadatmand S, Bretveld R, Siesling S, Tilanus-Linthorst MMA. Influence Of Tumour Stage At Breast Cancer Detection On Survival In Modern Times: Population Based Study in 173,797 Patients. BMJ 2015;351:h4901. [95] Mariotto AB, Zou Z, Zhang F, Howlader N, Kurian AW, Etzioni R. Can We Use Survival Data From Cancer Registries To Learn About Disease Recurrence? The Case Of Breast Cancer Cancer Epidemiology and Prevention Biomarkers 2018;27(11):1332–41. (with supplementary Table 4). [96] Arleo EK, Monticciolo DL, Monsees B, McGinty G, Sickles EA. Persistent Untreated Screening-Detected Breast Cancer: An Argument Against Delaying Screening Or Increasing The Interval Between Screenings. J Am Coll Radiol 2017;14(7):863–7. [97] Welch HG. NEJM Screening Mammograms II, YouTube. October 13, 2016 Available from: https://youtu.be/IwoIBTJD1VQ. [98] Surveillance, Epidemiology, and End Results (SEER) Program. Table 4.7 Cancer Of The Female Breast (Invasive). SEER Cancer Statistics Review (CSR) 1975–2015 Available from: https://seer.cancer.gov/csr/1975_2015/results_single/sect_04_ table.07.pdf. [99] Breast Cancer Facts & Figures 2017–2018. Atlanta: American Cancer Society; 2017. [100] C.D. Lehman, R.F. Arao, B.L. Sprague, J.M. Lee, D.S.M. Buist, K. Kerlikowske, et al. National Performance Benchmarks For Modern Screening Digital Mammography:
5
Clinical Imaging xxx (xxxx) xxx–xxx
E. Schattner
[101]
[102] [103] [104]
Update From The Breast Cancer Surveillance Consortium. Radiology. 2017; 283(1): 49–58. E.F. Conant, W.E. Barlow, S.D. Herschorn, D.L. Weaver, E.F. Beaber, A.N.A. Tosteson, et al. Association Of Digital Breast Tomosynthesis vs Digital Mammography With Cancer Detection And Recall Rates By Age And Breast Density. JAMA Oncol. 2019 Feb 28. H.G. Welch, Opinion: Mammograms Can Help–And Harm - CNN, November 20, 2013, Available from: https://www.cnn.com/2013/11/20/opinion/welchmammogram-robach/index.html. Aschwanden C. The Case Against Early Cancer Detection. FiveThirtyEight November 24, 2014 Available from: https://fivethirtyeight.com/features/thecase-against-early-cancer-detection/. Gawande A. Overkill. The New Yorker; May 11, 2015.
[105] Knox R. With Cancer Diagnoses, Better-Off Americans May Get Too Much Attention, Commonhealth: WBUR. June 8, 2017. [106] Welch HG. Treatment. The Heterogeneity Of Cancer. Breast Cancer Res Treat 2018;169(2):207–8. [107] Valencia OM, Samuel SE, Viscusi RK, Riall TS, Neumayer LA, Aziz H. The Role Of Genetic Testing In Patients With Breast Cancer: A Review Role Of Genetic Testing In Patients With Breast Cancer Role Of Genetic Testing In Patients With Breast Cancer. JAMA Surg 2017;152(6):589–94. [108] CDC. Groups At Higher Risk For Hereditary Breast And Ovarian Cancer: Centers For Disease Control And Prevention Available from: https://www.cdc.gov/cancer/ breast/young_women/bringyourbrave/hereditary_breast_cancer/higher_risk_ cancer.htm.
6