The Task Force Strikes Again — NEWS 5/09/23

Until 2009, few clinicians had heard of the U.S. Preventive Services Task Force (USPSTF), but in fact, they’ve been around since 1989 when they first endorsed screening mammograms, starting at age 40. The controversy about the “starting age” actually began in the late 1960s, and was already a hot topic for debate in the 1970s. Professional organizations were split down the middle, half favoring 40 and the other half favoring 50 as the starting age (supposedly based on data, not emotion)

The Task Force was conceived as an independent group of experts in public health and screening programs. Today, 16 members monitor over 100 screening recommendations for all sorts of diseases, with updates every few years. The Task Force is quick to point out that they are not a governmental agency, but they are funded by the government, with oversight by the government, so what does it matter? To complicate things, members rotate through the committee with relatively short terms, which might explain their remarkable inconsistency with regard to breast cancer screening. For breast screening recommendations, the USPSTF tries to update their position every 6-7 years, based on “new evidence.” Yet, if you read closely, that “new evidence” is often related only to the harms of screening (such as psychological trauma with a benign biopsy). Meanwhile, the benefits are calculated using obsolete data from primitive mammography used in the historic trials of the 1970s and 1980s. “Well, it’s all we’ve got,” they announce pitifully, while ignoring a mountain of data that supports screening average risk women beginning at age 40.

And while few had heard of the USPSTF in 2002, everyone heard by 2009 when they shocked the breast cancer community (and the world) with “Start mammograms at age 50, then every 2 years.” Those who understood the impact quickly calculated how many women would die unnecessarily each year due to these recommendations (“many thousands” for purposes here). So, by following the rules of “good science” and “evidence-based medicine” here’s what the USPSTF has done to make fools of themselves with regard to screening at 40 vs. 50:

1989 — start at 40

1996 — no policy, 40 or 50 is fine

2002 — start at 40

2009 — start at 50 and screen every 2 years

2016 — same as 2009

2023 — start at 40 and screen every 2 years

Meanwhile, other organizations (including the American Cancer Society) said “start at 40” throughout the entire controversy. Only recently, did the ACS switch to 45 to try and mediate the bitter arguments generated by the USPSTF. Of course, the American College of Radiology has maintained “start at 40” throughout the decades, but sad to say, no one trusts experts anymore. They are allegedly biased for their own personal gain, so insurers pay no attention to them. But what about “mostly neutral” organizations like the American Society of Breast Surgeons who make no money through screening programs? Doesn’t matter. They’re “friends” of the radiologists, and they can’t be trusted either. (Point of information and disclosure: I was a member of the most recent Screening Guideline Committee of the American Society of Breast Surgeons, and our group was nearly unanimous — “start at 40 with annual mammograms”).

The American Academy of Family Physicians, however, strongly (blindly?) endorses the USPSTF, as does the American College of Physicians (internal medicine specialists), making it so hard to battle the USPSTF that my own hospital in 2009 began telling its employees to wait until age 50 to begin screening (while I’m serving at the national level, endorsing 40). And I can assure you my hospital didn’t give a rip about what I said, or what Dr. Stough said, because the employee guidelines were drawn up by members of the American College of Physicians (read: USPSTF), located at the St. Louis hub, who voted along party lines — hook, line, and sinker — for age 50.

Screening is far more complicated than most imagine. I became heavily involved as an advocate of MRI screening, which was tied to risk assessment and genetic testing. I even started writing a book on MRI screening, getting about halfway in my efforts when the 2009 tsunami hit, and we went from 40 to 50. I abandoned my MRI intent, seeing a greater need to clarify screening in general, including the history of breast cancer screening, and how deeply flawed the USPSTF was in their assessment. When I finished, my publisher asked me to provide 10 possible titles for the book. They rejected all 10, not wanting to see “MRI” in the title. They renamed my book, “Mammography and Early Breast Cancer Detection: how screening saves lives.” Even today, I don’t know of any book that covers the controversy like I did. Sadly, few have even heard of the book, but I’ve received personal comments from experts around the world. One retired academic radiologist from the University of Manchester, U.K. wrote this: “I wish I had this book back when I was training residents in breast imaging. Everyone doing breast imaging should read it. To be honest, even I didn’t fully understand the controversies and complexities surrounding screening.”

There’s a huge difference between the skills needed to interpret mammograms and the epidemiology behind general population screening. Most practicing radiologists are unaware of the theories of screening and how statistics can be twisted. They might be superb at identifying cancer on a mammogram, but that has nothing to do with a controversy like “overdiagnosis.” But by the same token, the epidemiologists and others of the Task Force ilk do not understand breast radiology, leaving them often with empty-headed opinions.

Yes, you can use high-powered stats and sophisticated means of twisting those statistics to assess both the BENEFITS of screening and the HARMS of screening. But after the necessary calculations are made, and you put the two on a scale…they cannot be balanced! It’s entirely subjective at this point. BENEFITS vs. RISKS. How many benign biopsies does it take to neutralize the benefit of an early detection? It’s the final balancing act that keeps this controversy from being purely scientific.

I learned about the 2023 Task Force update like most everyone else — watching the evening news, then online coverage. Sounded simple, and as the USPSTF committee member told us about the NEW guidelines, it was crocodile tears as far as I was concerned (“We must be attentive to the fact that breast cancer incidence is increasing in younger women.” But who abandoned those women in 2009?).

Another neglected issue: younger women often need more than mammography, i.e., ultrasound at a minimum and perhaps MRI. And yet, the Task Force has been irresponsible in ignoring the data we have now on ultrasound screening and MRI screening. Guess what the Task Force says about breast density….”no proof that there’s any benefit from adding ANYTHING to mammography in women with dense breasts — that means no 3D, no ultrasound, no MRI, no molecular imaging, and no to anything else you can think of.” That leaves digital mammography as the sole recommendation, yet of all the types of imaging I just listed, 2D digital mammograms are the WORST at detecting cancer, or scientifically speaking, 2D mammograms have the lowest sensitivity for cancer detection among the wide array of options. And THAT’S the recommendation of the Task Force. I consider their approach to dense breasts to be an act of “malpractice by committee.” And if you think that’s harsh, there are applicable words that make “malpractice” sound soft. The Task Force has done more to harm breast cancer screening than any other organization — even more than those mammography-deniers who don’t believe mammograms save ANY lives. The difference between the Deniers and the Task Force? The Task Force claims, “We’re the authority on this, and we’re here to help you.”

The emergence and adoption of breast cancer screening is a remarkable story of the power of human bias. So, rather than the MRI book I had envisioned, it ended up being a book about screening for breast cancer in general, a soap opera when it comes to the history that continues to this day. Although the genre of the book is classified as “medical text,” it’s anything but. It’s human drama, the same as my novels. Sadly, the book got stuck with a bad title and a bad cover. But as one reviewer said, “In this era of doing less screening, Hollingsworth makes a convincing case that we ought to be doing more, not less. And for sheer entertainment, don’t miss the Endnotes.” (In fact, I had placed what became endnotes in the text itself, spicing up the story. But the editor supervened again, and pulled out many of the juicy tidbits and placed them in the Endnotes).

As I review my Task Force critiques throughout the years, I find THREE Powerpoint talks that I used to give to physicians at CME courses — one talk is 30 minutes, one is 45 minutes, and the one I preferred to give lasted a complete 60 minutes. Then, most of the book I’ve already mentioned is tied to the same topic. And finally, many of the essays in my book The Best Breast Blogatorials cover the Task Force and their wily ways. So, to make sure crocodile tears on the evening news don’t sway you, read one or both of my breast cancer books.

PS: I’m having trouble providing links in this Blog template, so the Blogatorial book will need a search using the title/author.

Breast Density in the Headlines Again

On March 10, 2023, the FDA issued a rule making it a requirement to send letters to patients undergoing screening mammography to inform those who have dense breasts. Where do I begin? After all, my professional study of mammograms that miss cancers dates back 30 years with my first academic paper: “Establishing a Histologic Basis for False-negative Mammograms,” published in the American Journal of Surgery….and the only publication of mine that was ever honored later as “One of the Top Contributions to Oncology in the Past 50 Years” by the same journal in a later anniversary issue.

Funny thing, though. At that time, I was focused on the impact of histology of various types of breast cancer, that is, what tumors look like under the microscope. And it was clear that some tumor growth patterns escape detection by mammography because they grow diffusely, without forming a “mass.” That publication was only the second time that “invasive lobular” cancer had been implicated in false-negative mammograms (common knowledge today). And, we made brief reference to the additional theory that tumors might be missed on mammography due to breast density. Only a few authors had raised this question….in 1993.

Long story short, in writing that first article, I wanted to start off with what was known about mammographic sensitivity, that is, the percentage of cancers detected. To my dismay, I could not find the reference that supported the oft-quoted, official, widely accepted… 90% sensitivity. I’ve chronicled this search in my books, and more recently, as the most comprehensive coverage of the story, written in a review article published in the American Journal of Surgery (same journal as above, circling back from my first publication). It’s a fascinating story of scientific paralysis, where the medical community refused to accept the true miss-rate of screening mammograms, a problem that continues to this day.

The question of missed cancers was hard to answer back then: How do you know you missed a cancer if it’s not on the mammogram? Quick Answer: you don’t. Instead, they used arbitrary follow-up periods, usually one year — any cancer appearing quicker than one year after a negative mammogram was a “miss.” It would take many pages to explain why this was an absolutely terrible way of judging sensitivity. But when breast ultrasound was introduced, the cracks in 90% started to form, and by the time breast MRI was introduced to the clinic in 2002, the belief in 90% was shattered (for many, but not all). If MRI is compared to mammography head-to-head, then we discover the chilling truth that mammograms miss 60% of cancers. That’s right, the number is remarkably similar from study to study. The sensitivity of mammography is only 40% when compared to MRI….and that includes all levels of density. If we restrict this to Level D density (extreme), then mammographic sensitivity for these women is around 20%. Stated alternatively, if mammograms tried to get FDA approval today, they would be rejected for Level D women and perhaps Level C as well.

When breast MRI first came on the scene, the “father of breast MRI,” Dr. Steven Harms, asked me to join his team of radiologists who educated the rest of the country’s radiologists on the use and interpretation of breast MRI. We traveled to so many cities I can’t even recall where. Nevertheless, one of my jobs as the token surgeon was to “crack the 90%”…”Do that 90% thing you do about mammography” wherein I would share the bizarre story of how we ended up with a grossly exaggerated number that doctors and patients grabbed onto, then refused to let go.

Back to the FDA. What are they doing sticking their collective noses into how we report screening mammography results? Well, little known fact — breast imaging became the first radiologic test governed by the FDA in the early 1980s. Sad to say, when mammograms were introduced in the 1970s, “mammography factories” opened up, and did a terrible job of quality assurance. Horror stories were often exposed on the evening news. The FDA took over, and still to this day, every breast center has to be FDA approved, then undergo a yearly inspection.

Here’s where it gets weird. For years, through state legislation (Oklahoma passed its law about 5 years ago), nearly every state in the Union already had this legislation in place (hard to believe it required legislation of any type, isn’t it?) So, the FDA has made it 100% (all states) and has standardized the reporting. So what? The final few states now have to comply, but that’s about it. There are no guidelines for these women who are left floundering, and are not counseled accordingly. It’s not an easy subject, and I won’t dwell on the mountains of misinformation that are out there for women with dense breasts. Oh, yes, the American College of Radiology issued guidelines, recommending the addition of breast ultrasound to mammography for women with Level C and D mammography, and this is all well and good. Problem is, we live in an upside-down world where the expert providers of medical service are not allowed to establish their own guidelines because of “known bias.” So, neutral organizations have to take the leap and confirm the need for additional imaging in women with dense breasts because third-party payors won’t pay attention to the expert clinicians.

Now, let me take it to a different plane. A few states (e.g., Connecticut) have lobbied for insurance coverage for screening US added to mammography for women with dense breasts and have WON. Great. But compliance is a huge disappointment (they might be up to 25% by now). Everyone drank the Kool-Aid of 90% sensitivity for mammos years ago, and now, even when covered by insurance, women settle for mammograms alone, and ignore those who are shouting: “Mammograms are not enough!”

This is why, btw, that I continue blood test research (currently with Syantra, Inc) so that women who have settled for mammograms alone will be inspired to proceed with additional imaging if the blood test is positive.

With my research career still active, we are ramping up for a definitive clinical trial of SyantraDX in high-risk and/or high-density women with normal mammograms who would then undergo additional imaging if blood-test-positive.

My coverage of the true complexity of the breast density problem and the fascinating history of the 90% can be found elsewhere on this web site, or in either of my two breast cancer books. It’s a fascinating story, especially the breakthrough in awareness that began with a grassroots movement prompted by one woman whose mammograms failed her miserably. Read about it here:

Mammography and Early Breast Cancer Detction: how screening saves lives

The Best Breast Blogatorials (essays taken from this web site)

I continue to fight the fight. MRI breast cancer screening guidelines were flawed from the beginning in 2007, and I’ve tried my best to draw attention to major issues that need to be corrected. I even served on the Screening Guideline Committee for the American Society of Breast Surgeons, and still couldn’t conjure any major changes. My major point is that breast density barely fits into screening algorithms, in spite of all the attention it gets today. But if you’re proposing a two-method imaging strategy, shouldn’t the first question be: “What is the probability that mammograms will fail?” That probability is based on density…yet the question is never asked using current guidelines. Instead, density is relegated to a modest risk factor (which is unrelated to whether or not a cancer will be found on MRI).

Evidence that clinicians are coming out of hibernation on this issue has finally arrived — The DENSE trial in The Netherlands is now reporting results greatly favoring MRI over mammography based on a single criterion — breast density. If you have Level D mammograms, you qualify. Very simple. And from that trial, the European Society of Breast Imaging, in 2023, changed MRI screening guidelines to include women with no other risk factors than Level D mammograms, to be done every 2-4 years in addition to mammography.

This idea of extending the intervals for MRI for women at lower risk levels (although density is a modest risk in and of itself) was first proposed in 2008 where a point system gave equal weight to density and to risk. In this system, the points are added, and the total number dictates the interval for MRI — every 1, 2, 3 years or not at all. This point system was published in Seminars in Breast Disease (now defunct) by my radiologist colleague, Dr. Rebecca Stough and me in 2008, a full 15 years before these new MRI screening guidelines with longer intervals from Europe.

At the time, we had our initial experience with MRI to go on, but after that, it was common sense, often dismissed as “weak” rational thought in this era of evidence-based medicine. That said, our system that focused on density yielded DOUBLE the number of MRI-detected cancers as the American Cancer Society’s guidelines. Those 2007 guidelines from the ACS remain the same. Oher organizations in the U.S. have made modifications to the original, but have not corrected most of the issues we have brought to light in a series of critical editorials.

A few weeks ago, we had an Editorial published in the online journal CUREUS, calling for a complete overhaul of the MRI screening guidelines in order to allow density to play a greater role.

Here’s the link to the new article about breast density and MRI guidelines: bit.ly/3Mh22uz

ABH

PS: I wonder if there has ever been simultaneous publication of a medical article and a medical novel at the same time? If you’re more interested in my novels, esp the new trilogy by “John Albedo, here’s the link to the book trailer: https://bit.ly/3lzaRot

VIDEO PODCAST

This podcast — “Gab Talks” — is sponsored by the New York City Big Book Awards, a service for winners and “distinguished favorites” in the 2022 contest.

Over the course of a half-hour, Gabby interviews “John Albedo” (Alan B Hollingsworth) covering 45 years of writing, dating back to that first novel that was never published, then to Flatbellies and on to the current Brainbow Chronicles, a trilogy starting with the award-winning NUTSHELL.

Click here for the podcast: https://www.youtube.com/watch?v=N4chEeqoWdc

Press Release (9/26/22) — NUTSHELL

Category: General Fiction

Scope of Contest: International, All Publishers

One Winner per category, with 4 Distinguished Favorites

nutshell-22-nyc-pr-dfDownload

50+ Cancer Types Detected with One Blood Draw?

BACKGROUND: Since the 1800s, pathologists have reported seeing malignant cells floating free in the blood stream of cancer patients. However, the technology to find extremely low numbers of circulating tumor cells (CTCs) is more recent, starting about 15 years ago when the term “liquid biopsy” emerged. The next step was new technology that allowed detection of “tumor DNA” (tDNA), or fragments of DNA that “leak” from cancer cells and can be detected in the bloodstream. The implication is that cell death has occurred, releasing the tDNA. (Note: a patient can have “cell free DNA” which is not from a malignant tumor, rather from cells that die normally). It became apparent that tDNA in the bloodstream might be better than CTCs when it comes to using “liquid biopsy” for cancer screening. (NOTE: there are other uses for tDNA besides screening — monitoring for recurrences, residual disease checks, guiding specific therapies. However, I am focused here entirely on asymptomatic screening).

In 2016, the company GRAIL was formed through financing strategies that included Jeff Bezos and Bill Gates, eventually raising over 2 BILLION dollars, with multiple studies launched using this new technology in several hundred thousand patients. One of these studies resulted in the Galleri blood test that can detect more than 50 different types of cancer. Galleri is not the only test available for tDNA, but for practical purposes, we’ll focus on Galleri.

FULL DISCLOSURE: Since I have been heavily involved in development of a blood test for breast cancer (only 1 of the 50+ cancer types from Galleri), I have had to follow the developments in this space closely ever since the inception of the technology. Furthermore, I am a consultant for Syantra, Inc., a Canadian company that is in the process of releasing their breast cancer blood test across Canada. And while it might seem that our blood test is in direct competition with Galleri, this is not the case. In fact, there is no contest between our single cancer approach versus the breast cancer data from Galleri. When the tDNA data started to emerge for breast cancer, it became quite clear that breast cancer does not “leak” its DNA reliably enough for early detection. So, we forged ahead using a different, albeit longstanding, approach — that is, circulating biomarkers — proteins that reflect the presence of cancer cells, in this case, specific proteins for breast cancer. So far, we chose the correct approach, though who knows what technology might be in the works? So, is Galleri the long-anticipated blood test for breast cancer I’ve been working on for nearly 30 years? No. (Other cancer types are another story — see Addendum).

MEDIA ANNOUNCEMENT: The reason I’m writing about this is that Mercy Hospital announced through a multi-media approach that it would be offering the Galleri test. This came from Mercy Central in Missouri, where many policies are established for the network hospitals and physicians. As you might imagine, I had people contacting me to see if the Galleri test had any relation to my research at Mercy where we had shipped 10,000 samples to researchers around the world (the Galleri test, by the way, is based on 20,000). The answer is: No. But my question is: “Why the middleman?” Galleri doesn’t need a hospital-based program. It’s been available by home kit for nearly a year. All you need is a registered physician-provider who agrees to write the prescription for the test, then the kit is sent, blood drawn at any lab (22 approved sites within a 20-mile radius of my home), then the physician gets the report. What does Mercy add? I don’t know, but the Galleri folks are experimenting with new business models, so I suspect there’s a “deal” that’s been made, and the question will be — who benefits? Does the patient get a discount on the nearly $1,000 cost if they go through a Mercy physician? If so, then great. But call me a “doubter.”

ABOUT GALLERI: The test is valid and extremely accurate — that is, extremely accurate for one of the two properties we need for early cancer detection using a blood test. Those 2 properties are SPECIFICITY and SENSITIVITY. In lay terms, Specificity is how well a test can identify true negatives through a low false-positive rate (confusing, I know, but hang in there). This is where Galleri shines. In medicine, Sensitivity and Specificity are often a teeter-totter — improve one side, and you lose on the other side. We like to see values above 90% for both Specificity and Sensitivity. Galleri boasts the remarkable Specificity of 99.5%! When you think about it, though, if you identify circulating tumor DNA, then there ought to be a cancer somewhere. So, in terms of “Positive Predictive Value” (PPV), a function of Specificity, Galleri is basically saying, “If you test positive, then cancer is present.” This is a luxury in screening because the great bugaboo in screening is the high “false-positive rate” that sends us scrambling on wild goose chases looking for what caused the “positive.” And then, there might be nothing, except continued anxiety for the patient. (Example: the callback and/or biopsy after a mammogram that turns out to be nothing.) With Galleri…virtually no false-positives!

But on the other side of the teeter-totter…things are not as bright. Sensitivity is how well a test can identify true positives through a low false-negative rate. Simply stated, Sensitivity is percentage of cancers that are detected by the screening tool. You can have very high Specificity and low Sensitivity, or vice versa, or both high, both low. Usually, the more the teeter-totter moves up, the other end moves down. And it’s the Sensitivity that is lacking in Galleri for many of the types of cancer being tested.

Across the board, for all tumor types, the Sensitivity is a rather low 51.5%. That is, Galleri is only picking up half the cancers. “That’s better than nothing,” you say. Yes, but that’s not the whole story. You see, there is another variable at work here — How early is the test picking up cancer? Are we talking about 51.5% Sensitivity for tiny breast tumors found on MRI? No. The 51.5% is for all stages of cancer, including advanced Stage 4 disease. So, breaking down into Stage at the time of detection, Galleri only detects 16.8% of Stage I cancers, the stage where most likely lives will be saved. Stage 4 — 90.1% Sensitivity, but that doesn’t help anyone. (That 16.8% is probably the most important number to remember in this post.)

These concepts are foreign to most, sometimes even confused by clinicians. So, let me explain by illustration the difference between Sensitivity and Specificity: Imagine 100 circles, 90 of them empty, and 10 of them colored in. The colored circles represent 10 patients with cancer, unknown to anyone, and no screening planned. Our job is to use a blood test to find those 10 cancers from the group of 100. We take samples of blood from all 100, and we have 5 positives, and all 5 turn out to have cancer. That gives us a Positive Predictive Value (derived from Specificity) of l00%. That is, when the test was positive, cancer was present 100% of the time. This is perfect Specificity at work. Great news that there were ZERO false-positives, so no wild good chases. However, notice that we missed 5 of the cancers. Enter a different blood test that has better Sensitivity, and in this case, positive results return for 9 of the 10 patients with cancer, for a Sensitivity of 90% (9 out of 10 colored circles identified). But the very properties that allowed the test to find 9 of 10 cancers spills over to the patients without cancer (those with empty circles). And, as it turns out, there were 20 positive results, with only the 9 having cancer. Thus, 11 patients get a false-positive prompting medical imaging or other testing trying to find the cancer. But there is no cancer. Even after a clean bill of health, the patient will likely worry. The false-positive rate is the great downside of screening for any type of cancer.

So, Galleri is in a bind as to how they market this test. Certainly, there is different Sensitivity for different types of tumors, with 18.2% for kidney cancers detected, but 93.5% for lung cancers detected. But then break down into Stage, and the lack of early detection is bothersome, the very thing for which Galleri is promoted. Breast cancer is one of the 50, but is not featured in marketing efforts. Why? The Sensitivity for Stage 1 disease is very low. In an effort to combat this result, the PR points out that early breast cancers must not leak very much tDNA, and this is probably indicative of a low-grade tumor that might be “overdiagnosed” through mammography, that is, a tumor that would never harm the patient. It might be true that only high-grade breast cancers leak their DNA early, but this is a long way from scientific corroboration. And when using such conjecture to cover a poor result, one is left with the unsettling interpretation — “With our test you won’t have to worry about overdiagnosis because our test doesn’t diagnose very many breast cancers anyway.”

Once upon a time, in order to introduce a screening modality, you had to prove a mortality reduction. This is why the U.S. Preventive Services Task Force won’t endorse much of anything when it comes to customizing breast cancer screening. But those days have softened by allowing surrogates, such as fewer interval cancers, fewer advanced stage cancers, etc. But what we have devolved to now is the mere detection of early cancer, the standard that many laypersons have held all along. But when it comes to early breast cancer, the tDNA tests (remember, there are other companies with similar results) are mostly finding Stage II and above, and even then, with lower sensitivities than other cancers. If the tumor cells don’t leak DNA, the cancer won’t be found by using blood.

Back to the overall Sensitivity of an unacceptably low 51.5% with Galleri…the PR has been presented cleverly to minimize this disconcerting number. Instead of the overall number, the Sensitivity figure is presented on the web site as 76%. And this would be good if it were for early-stage disease in all cancer types. But it depends on the type. It depends on the stage. And to show how the numbers game is played, the 76% has a qualifier — it applies only to those cancers which cause 2/3 of the cancer deaths. Okay. Fair enough. But those same cancers are more aggressive, and using the “conjecture approach” one could theorize these aggressive cancers are least likely to be affected by so-called early detection. Example: Does finding an unknown pancreatic cancer at 2.0cm yield a better outcome than a 4.0cm pancreatic cancer? Maybe. Or, maybe not. Pancreatic cancer often spreads very early in its course. This question is only settled through prospective, randomized screening trials that are decades away, if they happen at all.

Another maneuver in the numbers game is to focus on ACCURACY. “Accuracy” is not a lay term in this context. Accuracy is one of the 5 major performance characteristics of any screening test — Sensitivity, Specificity, Positive Predictive Value, Negative Predictive Value, and Accuracy (note: Galleri has the data for all cancer types, each type with 5 or more characteristics). Accuracy is the COMBINATION in formula form, of Sensitivity and Specificity, each providing half the weight. Thus, if a test is very strong in one or the other, it can “hold up” its sister concept and smooth things over. Never a better example than Galleri. An incredibly high Specificity holds up a very low Sensitivity, and we get an official Accuracy of 89%. Great! Only it’s misleading. PR knows that Accuracy is assumed to be Sensitivity by the lay public who really want to know: “If I have cancer, what are the chances it will be found by this test?” That’s not Accuracy the public wants to know…. it’s Sensitivity. Yet, when a layperson reads 89%, they would never guess that Galleri is only finding half of the cancers, and only 16.8% of Stage 1 cancers.

A blood test should be used in tailor made fashion based on its performance characteristics. High Specificity implies different utilization than High Sensitivity. This has been so confusing in my 30 years in this space that I wrote what might be the only “What if” article ever published on breast cancer screening and how a blood test fits into the picture. Not only do we have to deal with performance characteristics with a blood test for breast cancer, but also how does it fit into our current algorithms that are based on 3 different forms of imaging. (Reference: Hollingsworth et al, Modeling the Impact of a Screening Blood Test on the Use of Adjunct Breast Imaging. Breast J 2019; 25:1045-1046. doi: 10.1111/tbj.13397 )

And one final and very important point — Saving lives through screening (morality reduction) is based on a deceivingly simple formula: Vulnerable Biology + Sensitivity = Mortality Reduction. The cancer you are trying to find early must have a biology that lends itself to early detection. Some cancers are so indolent, they will be cured with or without screening. Others are so aggressive, they will not be cured even if found “early.” But those with a Vulnerable Biology lend themselves to early detection. That said, your screening tool must have good Sensitivity, that is, must find a large percentage of the cancers. And the greater that percentage…the greater the mortality reduction on the other side of the equation above.

NOTE: Specificity is NOT PART OF THE EQUATION. Specificity and Positive Predictive Value and Disease Prevalence are critical for screening feasibility, cost effectiveness, minimizing false-positives, etc. but they have NO impact on whether or not lives are saved. So, when I read this sentence from Galleri justification for its low Sensitivity numbers, I groan: A multicancer test like Galleri “with only moderate sensitivity but very high specificity and aggregate prevalence could detect more cancers than a single-cancer test with very high sensitivity but lower specificity and disease prevalence.”

I would love to see that last sentence translated to English, then run the numbers and show me how more lives will be saved by diagnosing fewer cancers. Again, the equation is remarkably simple — Sensitivity Alone dictates saved lives once a vulnerable biology has been established. For breast cancer, the “vulnerable” biology was established in the historical mammography screening trials. So, from here on, anything we do to improve sensitivity should save more lives. And for now, our best hope is a single cancer test that, when positive, tells the woman with normal mammograms that she should also have an ultrasound or MRI.

Ironically, my collaboration with 13 different biotech companies and academic institutions over the course of the past 30 years culminated in a large blood biobank at Mercy–OKC. Because we followed protocols to every detail, our samples were repeatedly noted as “superior” to commercial biobanks. But what really set us apart from the rest of the world was the fact that our blood was tied to MRI results. So, a “normal” was really normal. Word spread over the years such that our blood and our data was in great demand. And, after repeated failures in 3 clinical trials, we seem now to be on the verge of a blood test revolution. And the irony? Mercy–OKC shut down my research and my high-risk program two years ago, shortly after I was asked to play a leadership role for Syantra, introducing their test in the United States. Hopefully, we’ll get things going again in the U.S. with the emergence of a new breast center under construction now at SW 89th and I-44 in OKC.

END

ADDENDUM: It didn’t take long for someone to contact me and ask, “What about the other 49 types of cancer?” Here, it’s a different matter, especially if we’re talking about types of cancer for which there are no routine screening recommendations (as the company points out).

I think guidelines will emerge for “liquid biopsy” screening (and they’ll change as the technology improves), but it’s a personal decision to undergo this type of testing in the absence of a family history, with the understanding that a “negative” result does NOT assure one that cancer is NOT present. On the other hand, a “positive” result means cancer is very likely present (99.5%). Now, if a healthy person at baseline risk decides to do the test every year, or every other year, I think the benefit might become more evident over time.

However, for now, I think the test is a best used in those patients with a strong family history for various types of cancer where there are no current screening guidelines. We see this in our genetic testing program where families will have 3 or 4 or more types of cancer in the family, yet the genetic test is NEGATIVE. To me, this is the ideal use for the Galleri test.

As for those who test gene-POSITIVE for a cancer predisposition, it would depend on which organ systems are involved by the mutation. If breast cancer is the only site where a specific mutation increases risk, then there’s no use for Galleri if the patient complies with screening recommendations. But most of our gene-positive patients have more than one organ system for cancer predisposition. Again, if covered by current screening recommendations, then no need for Galleri. But if a genetic predisposition is identified, and the mutation involves a wide variety of possible cancer types, then Galleri is going to help, and we would make that recommendation (in fact, we would order the test for the patient as part of our high-risk program).

END

Encore

It’s been over 2 years since I last entered anything on this blog. With “retirement” due to the COVID pandemic, I went back to working on fiction — a trilogy — that I’d been intermittently working on for 20 years, ever since the publication of UNIVERSITY BOULEVARD. That trilogy — THE BRAINBOW CHRONICLES — is now in the final stages of production. That is, the first book was published in May 2021, the second in May 2022, and the third book will be released February 2023. (I will continue to devote half my time to breast cancer, serving in three consulting roles: 1) Breast MRI, 2) blood test for early detection, and 3) a new breast center in OKC, offering unique options.)

I’ve been asked how I could possibly crank out 3 novels, one per year. But the truth is, I wrote 3 books “at the same time, more or less,” completing my first draft of the trilogy about 15 years ago. Many changes have been made since the original version, but I’ve had the BRAINBOW CHRONICLES in my hands for a long time as I looked for a literary agent and/or a publisher. Black Rose Writing (Castroville, TX) was willing to take on the trilogy, understanding that the 3 books are closely intertwined, preventing anyone from offering a fair review unless the entire trilogy has been read. I’m pasting below a summary of the external, independent reviews to date. If you’re not familiar with this process of collecting “blurbs” for future book covers, keep in mind that Kirkus Reviews is one of the most well-established and respected services available for book reviews:

Praise for The Brainbow Chronicles:

THE BRAINBOW CHRONICLES (trilogy)

…a genre-bending series that is sure to keep readers hooked until the very end…an intriguing and enthralling trilogy…unprecedented insight… readers will become hooked on Chase’s story… The touch of supernatural sets the book and series apart from other medical fiction stories, keeping readers interested and engaged until the final page. (Entrada Reviews)

           

NUTSHELL

…a thought-provoking, emotionally rattling and gut-wrenching book (IndieReader — 5.0 starts)

…a fascinating story with all of the elements necessary to create great medical fiction (Entrada Reviews)

An in-depth, engaging look at the making of a physician. (Kirkus Reviews)

…the award-winning novelist writes with a deft hand, weaving together a myriad of storylines into a unified narrative – one that will leave readers guessing until the very last page. Add to that Albedo’s tempered prose and clear mastery over the subtleties of suspense and you have yourself a truly though-provoking page-turner.  (Vine Voice)                               

                                                                                                                               

CANNIBAL CLUB

…an enthralling story…Anyone who wants a glimpse into the life of a medical professional, including all of their flaws will enjoy spending some time with Chase in the second book of the Brainbow Chronicles. (Entrada Reviews)                                        

…when it becomes clear that Dr. Callaway has a “lethal rage” growing inside him, twists are afoot… A finely written character study of a multifaceted doctor. (Kirkus Reviews)

     

HEAVENLY BLUES

…once the work gains steam, it doesn’t let up. Unexpected, interesting topics abound…The final chapters do not disappoint.  (Kirkus Reviews)

The touch of supernatural sets the book and series apart from other medical fiction stories, keeping readers interested and engaged until the final page…readers will become hooked on Chase’s story…  (Entrada Reviews)                                                                                                 

END         

Exit Stage Left

5 years is a long time to write a monthly blog while never missing a deadline (self-imposed, of course).  Nevertheless, I’m done for now.

My favorite blogatorials (47 of 60) are now compiled into book form, humbly titled: THE BEST BREAST BLOGATORIALS (though some essays are not about breast cancer).

Link to Purchase e-book or softcover through Amazon Bookbaby:
https://store.bookbaby.com/book/The-Best-Breast-Blogatorials

I’m redirecting my writing to fiction.  It’s been almost 20 years since my novel Flatbellies was published, and I’m not sure I can equal that surprising success.  Still going to try, however.  Teaser for my work-in-progress, titled Nutshell — the setting is a medical school located next door to a mental institution, the story beginning in the 1930s

Alan B. Hollingsworth, MD

Contralateral Mastectomies – NO! But Preventive Mastectomies – YES?

A common thread in my scribblings are the inconsistencies, bias and logical fallacies that fly in the face of so-called evidence-based medicine – in other words, those situations where the p-value is great, but the conclusion foolish.

And one of those inconsistencies is the attitude – no, fervor – about contralateral mastectomy (yes or no) vs. preventive mastectomy, the former patient having one cancer, the latter having no cancer. I’m speaking about the party-line directive that minimizes risk of contralateral disease in one patient while maximizing risk of the first primary cancer in another.

When the “epidemic” of contralateral preventive surgery began, everyone rushed to blame somebody or something – e.g., patient ignorance, poor counseling by physicians who overestimate risk, overly enthusiastic plastic surgeons, pre-op MRI, etc. It was inconceivable that women would opt to have the other side removed electively when there was no survival advantage. (Of course, if survival is the only endpoint, we’re all in trouble).

These stunned critics of contralateral prevention were likely too young to have lived through a true surgical epidemic, that of subcutaneous mastectomies in the 1970s. Shortly after implants were introduced, many thousands of women had both breasts removed for pain and cysts alone (the much-dreaded fibrocystic disease) with only secondary consideration for cancer prevention (which failed because too much breast tissue was left behind in order to achieve optimal cosmesis).

As an aside, more than other organ systems, it is my contention that physicians – both female and male – project their own reverence for breast tissue onto patients and their desires, thus clouding the objective assessment of why patients do what they do.

“If women only knew what their true contralateral risk was, they wouldn’t opt for contralateral mastectomy so often.” One still hears this today, as if this decision is based on a single issue (risk level), in spite of all evidence that it is a complex multi-factorial decision, based on different reasoning by different people.

In a 1990 academic Morbidity and Mortality conference at the University of Oklahoma, shortly after I joined the faculty, one of the general surgeons noted, “What’s going on around here? It seems like all our patients are having either lumpectomy or bilateral mastectomy? What happened to the standard unilateral mastectomy?”

What was happening was an exhaustive informed consent in very knowledgeable breast cancer patients, younger than average, coupled to a cutting-edge reconstruction team that introduced pedicled TRAMs early on, then free TRAMS later. The majority of our mastectomy patients were reconstructed with flaps rather than implants. And since the flap approach was a one-time operation, we skewed the experience toward bilateral where both sides could be reconstructed symmetrically, although some still opted for unilateral surgery. Many other reasons prompted the choice for contralateral prevention, including an accurate risk assessment, but all of them legitimate in my view, always patient driven, and none of them related to a survival advantage.

But I digress from my main point:

My point has to do with the incredible inconsistency in practice today whereby we try to minimize the contralateral risk in a newly diagnosed cancer patient, while we maximize the risk for women with no history of cancer. Why?

I don’t know “why,” but consider this inconsistency. Breast MRI is widely accepted for high-risk screening in women with no prior cancer, but not routinely accepted (condemned by some) for the newly diagnosed breast cancer patient to check the opposite side. Yet, the probability of finding an unsuspected contralateral cancer with MRI is greater in the cancer patient (3-4%) than it is in the high-risk population (2-3%) or in the modest risk population where a great deal of MRI screening takes place (1-2%). Dismissive comments about pre-op MRI work best on the ipsilateral findings, but when contralateral cancer is found, it makes “leaving an untreated cancer behind” a reality, magnified in the DCIS patient who has an occult invasive cancer on the opposite side.

There are no “calls to action” to stop high-risk MRI screening — quite the opposite. We use mathematical models that often inflate risk beyond reality in order to maximize the probability that MRI screening will be covered by insurers — “anything” to reach that magical 20% lifetime, even though these models are not very accurate at the individual level (good calibration for cohorts, but only 0.7 c-stat for discrimination). Yet, in the process of overestimating risk (and through multi-modality imaging and its callbacks), we drive some women to preventive mastectomy. Where is the same outrage that we see with cancer patients opting for contralateral prevention?

In sharp contrast to the high-risk patient, we don’t overinflate contralateral risk in the cancer patient. In fact, we use numbers for counseling that are sometimes lower than reality, not too much different than baseline risk in a non-cancer patient. For instance, tables and tools tell us to use 0.5%/year in the typical ER-positive patient, but this number assumes total compliance with endocrine therapy when, in reality, only about half of women actually complete 5 years of endocrine therapy. Without this protection, the contralateral risk is at least 0.75%/year, maybe 1%/year in the ER+ patient (that is, without other supporting family history or gene-positivity). For a 40 y/o cancer patient, non-compliant with her endocrine therapy, that’s 30-40% lifetime risk of contralateral cancer, without considering the mortality rate of her first cancer…

(I always found it hard to say, “Your contralateral risk would be 30%, but…since you have a 50% mortality rate from your current cancer over that same course of time, the true risk that you’ll ever live to see a contralateral cancer is 15%.” So, I ignore the models that include mortality, and simply say: “Assuming you beat this first cancer, the odds that you will face a second….”)

We can ratchet up the risk level in high-risk (gene-negative) patients to numbers comparable to BRCA-positivity when tissue risks are coupled with Level D density, which are then coupled further to SNP scores. Since no one has actually observed, let’s say, 80% of women getting cancer based on atypia, Level D and SNPs, it begs a cautionary note: “Are we counting 3 different manifestations of the same thing?” Our mathematical models for the first primary are suspect without prospective validation. In contrast, our risk models for contralateral cancer are drawn from direct observation. Regardless, the push is to get that number as high as possible in the no-cancer patient for MRI coverage, and ignore the backfire that might send the patient toward preventive mastectomies.

So, we end up with this:

To the 40 year-old cancer patient: “Don’t worry about your opposite breast. The risk of getting cancer on that side is very low, only 0.5% per year or 20% lifetime, and it won’t improve survival if you remove it now.”

And to the 40-year-old no-cancer patient: “You are at very high risk for the development of breast cancer – 20% lifetime – and you should undergo annual MRI screening in addition to mammography. (Then, 5 years later, after high anxiety due to frequent callbacks and benign biopsies, she opts for bilateral preventive mastectomies.)

After 40 years of practice, I’ve had plenty of patients return with contralateral cancer to say, “I told you I wanted that other side removed.” I’ve never had a single patient say, “I wish I’d never done the opposite side.”

No Breast Cancer Risk Reduction with Risk-reducing Salpingo-oophorectomy?

It’s been 24 years since BRCA testing became commercially available, after sequencing was accomplished by the team led by Mark Skolnick (above).  And for 24 years, we’ve been telling BRCA-positive patients that bilateral salpingo-oophorectomy, if performed premenopausally, around age 40, will simultaneously reduce breast cancer risk…substantially.

But now…a multi-center prospective study of risk-reducing salpingo-oophorectomy (RRSO) was just published in Breast Cancer Research (https://doi.org/10.1186/s13058-020-1247-4), concluding no benefit for BRCA-1 patients when it comes to breast cancer risk reduction, and limited benefit for BRCA-2, perhaps increasing over time after the RRSO.

With more authors than I can count, merging multiple cohorts, using epidemiologic terms I’ve never heard before, e.g., “immortal person-time bias,” the results – if valid – are practice-changing for those of us who deal with high-risk gene-positive patients.

For those thousands upon thousands of women who have tested BRCA-1 positive since 1996, and who then opted for early-age RRSO and were told “you also cut your breast cancer risk in half”….SURPRISE – no benefit whatsoever! At least, that’s what this article is telling us, while simultaneously claiming to be the largest and most pure study ever performed. And I can assure you, from now on, many will be quoting “no benefit” for RRSO protecting against breast cancer in BRCA-1 patients without scrutinizing the study design. As always, the devil lives in the fine print.

Granted, one wouldn’t expect as much benefit in BRCA-1, given the ER-negative propensity, but zero benefit is unlikely. And, the benefit of RRSO for BRCA-2 when it comes to breast cancer risk reduction is likely going to be substantial in the long term (this prospective study had a mean f/u of only 5 years).

Here are my quibbles:

1) Counting cancers that occurred shortly after RRSO — if a patient developed breast cancer within 2 months, they were excluded. TWO MONTHS! That’s not near enough to exclude patients with established cancer wherein RRSO cannot possibly benefit. In fact, investigators should have excluded patients for the first two years after RRSO, not months, to truly measure a preventive effect.

2) Postmenopausal women were included. Now how exactly is RRSO supposed to prevent breast cancer in a postmenopausal woman?

3) In the Discussion, a point is made about how “HRT” could cause one to lose any protection from RRSO performed premenopausally.  Let’s consider that “HRT” can be either estrogen alone or estrogen plus progesterone. The prospective, randomized WHI study (see last month’s blog) has been telling us for many years that the two approaches have opposite effects – exogenous estrogen alone lowers breast cancer risk (and mortality) while E+P raises risk (and mortality). To lump these two opposites into “HRT” is misleading. It has always been misleading to tell BRCA+ patients that “HRT” will cause them to lose any breast cancer protection afforded by RRSO. Add-back HRT is lower (and often non-cyclic) than the natural premenopausal state so even in theory, one could make the case for hormonal add-back in low doses.  And now there is confirmatory data that little or nothing is lost when given to BRCA-positive patients after RRSO.

4) As Malcolm Pike, PhD and colleagues have shown us for 30+ years, the most powerful variable in endocrine manipulation when it comes to preventing breast cancer is the number of years of high, cycling hormone levels that can be shaved away through an early, induced menopause. Using age 50 as the predicted age when menopause would occur naturally, inducing menopause at 45 lowers risk a little, but 40 has a much stronger effect, and age 35 stronger still. And, consider that we counsel patients to have RRSO performed at 35-40 for BRCA-1 and 40-45 for BRCA2. These ages are chosen primarily on the age profile of fallopian tube/ovarian cancers. So, if 35 to 40 is the very strong recommendation for BRCA-1 patients, why did the investigators pick the single age of 45 with binary outcomes – above vs. below 45? Rather than stratify outcomes by age, a binary approach was used, based on an age that has no clinical relevance.

The study design would have been more helpful like this – exclude all cancers occurring within the first 2 years (or at least one year). And, stratify impact according to age groups as to when RRSO was performed: under 35, 35-40, 40-45 (no need to include over 45 at all, at least theoretically). Yet, in the binary approach of this study, there were 1,783 person-years over the age of 45 when RRSO was performed (including postmenopausal women) and 2,205 were under the age of 45.  We can say nothing about the impact of SSRO when performed at 40 or younger from this article.

While the study might give us pause for the BRCA-1 patients, as one would not expect the breast cancer risk reduction with RRSO to be as much as BRCA-2, we have to acknowledge that adjusting our risk calculations upwards might result in more preventive mastectomies. And maybe that’s the right thing to do, I don’t know.

I will probably adjust my counseling to a degree – that is, introduce more uncertainty about the impact of RRSO in the BRCA-1 patient when it comes to breast cancer risk. But for BRCA-2 patients who have RRSO performed around age 40, well, this current study doesn’t alter anything. We are counseling patients about lifetime risks, not 5 years, when it comes to making decisions about the age at which to perform RRSO.

END

(Will Rogers Airport, OKC) Hosting Mark Skolnick in Oklahoma City (1995), shortly after the sequencing of BRCA-1 and before Myriad Genetics was offering commercial testing.

Burying the Lead with an Axe (or How You Might Prevent Breast Cancer with Estrogen)

The headlines should have swept the nation and the world – ESTROGEN REPLACEMENT THERAPY LOWERS BREAST CANCER INCIDENCE WHILE REDUCING MORTALITY AS WELL. But you probably never heard a word about it. And if you did, you probably heard the distorted version that has tricked and befuddled many, ever since the Women’s Health Initiative began over 20 years ago – HORMONE REPLACEMENT THERAPY INCREASES BREAST CANCER RISK. What gives?

The media coverage from the Women’s Health Initiative (WHI) has been shaky for many years, not to mention widespread misunderstanding by clinicians, which then translates to a confused public. This is not helped by local newspapers where the story from the newswire services (Associated Press et al) might report the story correctly, but since the lead can be buried at the tail end of the press release, it often gets the axe (as happened in our ever-shrinking Oklahoma City newspaper), and doesn’t appear in print at all. A devoted search online will eventually lead to the facts, but filtering out the garbage can be very difficult.

Let me see if I can resurrect the mind-blowing results of the WHI that have been inexplicably ignored for 20 years.

The Women’s Health Initiative (WHI) was launched by the NIH in 1993 addressing several health issues with proposed interventions for postmenopausal women – heart disease, breast cancer, colorectal cancer and osteoporosis/bone fractures. Of several high-quality WHI clinical trials, we are interested here only in the impact of hormone replacement therapy on breast cancer risk and mortality. And here’s where the confusion begins – Estrogen plus Progesterone had the opposite effect to using Estrogen alone.

Yet, media coverage (and downstream public confusion) regularly lumps the two trials with very different outcomes into one all-encompassing (and incorrect) statement: “The WHI showed us that hormone replacement therapy increases breast cancer risk.” The error is generated by the phrase “hormone replacement therapy,” which covers different concoctions, far too ambiguous to use in this controversy.

I’ve even heard experts at the podium boast about the WHI as proof that “evidence-based medicine” dispels gross misconceptions, e.g., “We once thought that hormone replacement therapy was safe with regard to breast cancer risk, but the WHI showed us the dangers, and now that women have decreased their hormone use, breast cancer incidence is actually declining.” By the end of this article, you should be able to see the error in that seemingly benign statement.

Twenty years ago, I wrote the first lay book on breast cancer risk assessment. Well, more accurately, it was almost the first. Dr. Patricia Kelly’s book (Assess Your True Risk of Breast Cancer) was released one month before mine, and we both essentially wrote the same thing, independently. Yes, bookstores were loaded with tomes covering various risk factors for breast cancer, but the distinction is this – no authors of lay literature were combining multiple risks into a workable number from which patients could make rational decisions. This would later become known as “breast cancer risk assessment.” The Gail Model had been developed, but was largely unknown at the time except for its employment in the NSABP P-01 trial on tamoxifen prevention. Other models had been proposed in the epidemiology literature, but had not been recognized yet at the clinical level. Anyway, in that book, I distilled what was known at the time about hormone replacement therapy (HRT), and it was clear that there was a difference between estrogen alone (in women who had undergone prior hysterectomy) and estrogen plus progesterone (in women with an intact uterus).

Note: the progesterone is added primarily to protect the lining of the uterus from the non-stop estrogen effect, which can increase the risk of uterine cancer. Sadly, many patients back then were told that E+P would be good for reducing breast cancer as well (“just like the uterus”), but evidence was already available 20 years ago that indicated otherwise.

Although the available literature at that time was based on observational studies without prospective, randomized trials, there was a consistent feature – E+P was worse than E alone. In fact, I made the bold statement (bold in 2000, that is) that if you made the distinction between these 2 very different HRT approaches, future studies might prove that estrogen alone will carry no risk at all. This was nearly heresy. But I wasn’t relying only on available clinical literature at that time. I had reviewed the basic science literature as well. Histologic changes in breast tissue had been documented during different phases of the menstrual cycle, as well as various postmenopausal hormone preparations. Oddly, estrogen alone had very little impact on mitotic figures in the breast (or on other proliferative markers), which indirectly might translate to no increased breast cancer risk.

As it turned out, my prediction of E-alone as being “neutral” was not revolutionary enough. The WHI showed a lower risk of breast cancer in the E-alone limb from the git-go. And this finding was roundly ignored, with the entire focus placed on the E+P findings that prompted stoppage of this E+P limb of the study due to the increased breast cancer risk (the increased risk being a predetermined checkpoint that was actually a rather modest degree of risk, but nonetheless real). The poor E-alone findings of benefit got dragged down to the depths of obscurity even though the results were opposite that of E+P. In the end, it was all lumped together as HRT, in general, “increases breast cancer risk unacceptably.”

It is critical to understand that these were two separate trials within the WHI umbrella – 1) Estrogen (E-alone) vs. placebo and 2) Estrogen plus Progesterone (E+P) vs. placebo. Both were prospective, randomized trials, which have more power in defining truth than observational studies, even when those lesser studies are combined (selection bias in observational studies can only be limited through prospective randomization). 16,608 women participated in the E+P trial, while 10,739 participated in the E-alone trial. In the E-alone trial, women had previously undergone hysterectomy, thus eliminating the risk of uterine cancer in those women who take estrogen alone.

As noted above, when the initial report was released in July 2002, it prompted early termination of the E+P group as risks were outweighing benefits, led by the predesignated breast cancer risk. Even then, however, as “HRT” was widely blackballed, the results in the E-alone limb were surprising – there was a LOWER incidence of breast cancer. Experts dismissed the finding as it failed to reach statistical significance (though it was close), and the anti-E+P juggernaut continued, incorrectly absorbing results of both trials in its wake as a single finding in a single study (through no fault of the WHI, but through commentators on the trial).

But then something unexpected happened with longer follow-up – the E-alone women had fewer and fewer breast cancers emerge until that group did, in fact, reach statistical significance. AND YOU DIDN’T HEAR A WORD ABOUT IT! Why? I’m not sure, except that it didn’t make biologic sense (to most). The E+P findings made sense, and the risk was readily accepted. But the E-alone lowering of risk had no biologic explanation.

Improbably, E-alone appeared to be preventing breast cancer. Pundits continued to point out the wonder and beauty of evidence-based medicine in reducing breast cancer incidence through widespread stoppage of E+P, even though these same experts and journalists were simultaneously ignoring the shocking evidence in the E-alone trial. “Well, just give it time, and you’ll see that E-alone will eventually raise risk.” Or, so it was said by the few who actually had noticed the disparate findings between the two limbs.

In 2004, the E-alone trial was stopped as had been done previously for the E+P trial. But it was not because of breast cancer risk, which had landed on the benefit side of the scale. It was because of a small increase in strokes in those taking Estrogen alone over placebo. Without digressing too much, this stoppage was inconsistent with the SERM risk reduction trials where both tamoxifen and raloxifene demonstrated an increased risk of thrombotic events, but the chance of a breast cancer being prevented greatly exceeded this risk, allowing FDA approval for breast cancer risk reduction with SERMs. But the WHI had a different philosophy, largely because so many more women would be taking Estrogen if endorsed. Even though the risk of stroke was very small in comparison to overall benefits, they did not think a preventive medication should carry any measurable risk. For purposes here, the E-alone trial, unlike E+P, was not stopped due to the breast cancer risk.

But in December 2019, at the San Antonio Breast Cancer Symposium, Rowan Chlebowski, MD, PhD, stunned the audience with the 20-year follow-up for the TWO hormonal therapy studies of the WHI. The E+P results were similar to earlier reports – a 29% higher incidence of breast cancer, statistically significant, and a 45% increased risk of breast cancer death. It is here that stoppage of E+P (at least the combination used in the WHI – Prempro™) has likely spared many women the diagnosis of breast cancer. But in fact, this was nothing new. What was new about the E+P follow-up was the fact that the risk persisted even after stopping the hormones. In the first reports, this risk seemed to disappear, then later reports indicated some risk persisted, and now the long-term follow-up suggests the E+P risk to be more persistent than we thought after stopping therapy, perhaps lasting a lifetime.

But the “shock” came with the other study — the long-term follow-up in women who took Estrogen alone vs. placebo. The lowered incidence of breast cancer on estrogen was maintained and now clearly significant from the statistical standpoint – a 23% reduction in breast cancer incidence (remembering that E+P increased risk 29%). But much to the surprise of even Dr. Chlebowski, there was a statistically significant reduction in breast cancer mortality of 44% with the use of estrogen alone.

As Dr. Chlebowski pointed out, the FDA has approved two drugs to prevent breast cancer – tamoxifen and raloxifene – and neither of these agents has been shown to lower breast cancer mortality. Yes, both agents lower breast cancer incidence (slightly more powerful than the estrogen data above), but neither drug used in the preventive setting has yet been show to lower morality due to breast cancer. Only Estrogen fits that bill. Go figure.

Another oddity is that the reduced risk occurred primarily in estrogen-positive/progesterone negative tumors. How does taking estrogen reduce the risk of an ER-positive tumor? Because the story is much more complicated than what one chooses to take as replacement therapy, and the changes in ER status of individual cells likely take place largely independent of what hormone one takes above and beyond the natural milieu. Patients routinely state things like, “My mother’s breast cancer was estrogen-fed, so I’m not too worried about my family history since I don’t take estrogen.” This is faulty reasoning, and such a patient should acknowledge the family history independent of whether the tumor is “estrogen-fed” or not.

And another point: all the percentages above are referring to RELATIVE RISK, which can be very misleading. Relative risks are always more impressive than ABSOLUTE RISKS. An increase from one cancer to two cancers in a study would be a “100% increase” in relative terms. A decrease from two cancers to one, on the other hand, is a “50% decrease in risk” in relative terms. Relative risks are calculated without knowing the total number of patients in a study. Absolute risks include that number, offering far greater perspective in making therapeutic choices (and much lower numbers that aren’t as exciting).

For example, in the E+P study, there were 1,003 cancers overall, so if 438 cancers occurred in the placebo group, then a “29% increase in risk” would generate 565 cancers in the group that took the combination of E+P, or an excess of 127 cancers attributable to the use of E+P. But there were about 8,000 women who took E+P and did NOT develop breast cancer, so this excess of 127 cancers translates to an absolute risk of 1.6% that E+P will generate a breast cancer above and beyond baseline risk. This absolute risk might be acceptable to an individual trying to make a decision about HRT using E+P, but on the other hand, it is quite unacceptable to public health experts who translate that tiny number to the millions of women who were taking E+P at the time, prompting discontinuation of the study.

Turning to the E-alone study, there were 520 cancers in the long-term follow-up, so if 294 cancers occurred in the placebo group, then a “23% reduction” would leave us with 226 cancers in the group that took estrogen. But there were over 5,000 women who took estrogen in this study who did NOT develop breast cancer. So, the benefit was restricted to 68 women (294-226=68) out of 5,000, around 1.4%. Which is more impressive – a 23% relative reduction, or a 1.4% absolute risk reduction? Both are true. “Relative” wins the popularity contest every time, but it’s the 1.4% absolute benefit that gives you better perspective.

(Note: It was this sort of exercise – distinguishing relative risks from absolute risks – that Dr. Patricia Kelly and I introduced to the lay public, and many professionals, in our books published in year 2000. It’s hard to believe now, but very few studies made the distinction at the time. And while both books could make the reader math-weary, the bulk of information included was brand new to both the lay public and health care providers.)

One month has passed since the WHI announcement in San Antonio, and very little can be found even online about this landmark study. And when discussed more precisely in terms like “combined hormone therapy increases breast cancer risk and mortality, an opposite effect than single agent therapy,” the impact of this study can still be missed. That is, estrogen-alone replacement therapy might actually lower breast cancer risk and mortality. Few readers of current articles could explain exactly what “combined therapy” or “single agent therapy” is. Only rarely will you see a distinction made, using the culprit’s true name – progesterone (in combination with estrogen).

So, does the scientifically “pure” WHI study, with over 10,000 women in the E-alone study, trump the 100,000 women in the U.K. meta-analysis that combined 58 lower-quality studies where estrogen alone had a modest increased risk for breast cancer? Not all 58 studies showed increased risk, of course, but the combined meta-analysis revealed an increased incidence with estrogen, regardless of the exact preparation or whether oral vs. transdermal (only vaginal estrogen cream escaped implication). Hard to say.

Observational studies include a variety of built-in biases, such as “selection bias,” a phenomenon difficult to erase even with meta-analyses. For example, women who opt for estrogen replacement seem to be more compliant with routine screening mammography, and if so, more low-grade cancers will be identified – not because of a negative impact from estrogen but due to the “length bias” potential (call it overdiagnosis, if you must) of screening. Meanwhile, those not taking estrogen might be less likely to get mammography whereupon fewer cancers will be found.

As for me and my patients who ask about estrogen-alone replacement, I’ve been telling women about the WHI ever since their first announcement 18 years ago, using words like this: “The most scientifically pure study ever performed indicates estrogen alone is safe with regard to breast cancer risk and might even be protective against breast cancer,” often adding: “new studies might show different results, or that non-stop use for decades might negate the benefit seen with short-term use, but for now, it appears unlikely that you could do yourself harm with estrogen alone.” And if more information is requested, I go into absolute risk and benefit, as distinct from relative risks and benefits, especially if we’re talking about using E+P.

Although the story is still being written, my question is more than “Does estrogen alone actually prevent breast cancer deaths?” The more immediate question is: “Why is no one talking about it?”