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

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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

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(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?”

Just How Dense Are You?

 

Forty years ago, mammograms detected 90% of breast cancers. Or so we were told. Oddly enough, the more that the technology improved, the worse that mammograms performed. That is, the data on sensitivity started falling apart under scrutiny. The 90% became 80%, which more recently added this modifier: “…but with dense breasts, it’s more like 50%.”

Those of us practicing medicine in the dense breast space, or more accurately, the dense breast wilderness, have long known that the dense breast problem is much worse than both clinicians and patients have been willing to admit. In fact, for Level D density, 50% is a gift. Level D gets to hide behind the skirts of Level C, and when both groups are managed as one (the usual situation), then yes, 50% sensitivity works pretty well. But isolate Level D, and…ugh. The 10% of women with Level D have not been singled out for more specific information about the reliability of their mammograms when used alone.

At least, not until now. We’ve been eagerly awaiting the initial results of the prospective, randomized DENSE Trial from The Netherlands for several years. This is a unique study using breast MRI in women with Level D density. Very straightforward patient accrual strategy – Level D and you’re in. The study will be generating data for the next 10 or more years (including the stringent endpoint of a mortality reduction, the only endpoint recognized by the U.S. Preventive Services Task Force in breast cancer screening).

The interesting thing about these trials is that you can predict results fairly well with some basic information: Sensitivity of mammography in Level D patients, Sensitivity of MRI in Level D patients, and disease prevalence in the study population. For longer studies (DENSE is only 2 years of screening), you also need to know disease incidence. In the case of disease prevalence and incidence, one must remember that Level D patients are at a modestly increased risk for breast cancer, such that we face a double whammy – higher probability of cancer and higher probability that cancer will be missed if screened only with mammography.

It would have been nice to include Ultrasound as an alternative to MRI, but a 3-limb study requires many more patients and much more money. Nevertheless, it has been my view for a long time that for Level D patients (what we used to call Level 4, and what was originally called “extremely dense”) mammography alone is inadequate for screening and that supplemental imaging is mandatory for acceptable practice.

The current grassroots movement on breast density awareness would have done well to avoid the dichotomy of “dense vs. non-dense.” They should have come out swinging, stating: “Supplemental imaging is mandatory for Level D patients, and is strongly advised for Level C.” The Level D data would have poured forth freely, and as a result, it would have become obvious that mammograms are not enough. Gradually, this would have spilled over to Level C patients, or at least, selective Level Cs, and we would be where we need to be. As it is, we have a staggering amount of legislation that is largely edentulous because insurance won’t cover the supplemental imaging in most states.

It doesn’t help that the Task Force has ruled on breast density in one of the most ludicrous policies they’ve ever generated, that is – No evidence to support imaging the dense breast with 3-D mammography, ultrasound, MRI “or any other modality” beyond 2D digital mammography. It doesn’t matter to them that if one ranks all known breast imaging modalities according to sensitivity levels in dense breasts, mammography would come in dead last. For the Task Force, no mortality reduction equals no endorsement when it comes to breast cancer screening.  Though the DENSE trial won’t matter to the U.S.P.S.T.F. until the mortality data is available, at least we have the preliminary results for other endpoints.

Traditional risk factors didn’t matter one way or the other as the sole criterion for entry was Level D status. Kudos to the Netherlands for their design. All prior MRI screening trials have been based on risk levels (without a care in the world as to breast density). It could be claimed that the well-designed ACRIN 6666 took density into account, but not without traditional risk factors, and with its focus on ultrasound, while MRI was secondary.

To me, it’s always been a two-factor problem – the level of risk is only half the story. The other half of the story when discussing a second modality for imaging should be: “What’s the chance that the first modality will fail?” It is inconceivable how this second issue has been cast aside. It all started with the original 2007 guidelines for MRI screening from the American Cancer Society. There, breast density was treated like an isolated risk factor that “needed more research,” when, in fact, density should figure into the equation for recommending supplemental imaging in every single patient, high risk or not. Density dictates efficacy. And density is a feature that should be integral in our recommendations for supplemental imaging.

So what do we know from the DENSE trial preliminary data, published this past week in the New England Journal of Medicine https://www.nejm.org/doi/full/10.1056/NEJMoa1903986

Interval cancers were cut in half (from 5 per 1,000 to 2.5 per 1,000). This is a major point (in fact, it’s the primary endpoint in the study) because screening alone can find low-grade cancers which evoke accusations of overdiagnosis. If you are detecting clinically important cancers, then the number of cancers popping up in between screens must go down. Later, you also need to show fewer advanced stage cancers in the MRI-screened group. If you detect more cancers with MRI, but the interval rate stays the same and the advanced cancer rate stays the same, then you are likely detecting such low grade tumors that the patient would have done just fine waiting until her tumor was found on mammography or palpation.  In the end, however, both interval cancer rates and advanced disease rates are surrogates for the top priority — mortality reduction.

The cancer detection rate (CDR) in the mammography plus MRI group was 16.5 per 1,000 screened, approximately 4-fold the number ordinarily found with mammographic screening alone. So, if mammograms are detecting 90% of cancers, then MRI is detecting 360% of cancers? Of course not, but this is the incongruity we’ve been living with for years.

About 15 years ago, TIME magazine ran a spread on breast MRI screening, and within the article, it was clear that mammography was only detecting 40% of detectable cancers when compared to MRI. That’s 40% sensitivity. Then, in a sidebar about mammograms in general, the comment was made: “Mammograms detect 90% of breast cancers.” Where was the cognitive dissonance? I can’t figure it out. The dissonance didn’t seem to bother anyone!  There was apparently no cognition.

Pro-screeners have shot themselves in the foot on discussing sensitivity across all levels of density – the only way they can promote much-needed multi-modality imaging is to admit that, for many years, they have overstated the effective sensitivity of mammograms alone. And if we combine Level C and D, then we’re talking about misinformation for nearly one-half of the female population who opt for mammographic screening!

For the record, 3D mammography has been a much-needed leap in mammographic sensitivity, but still, ultrasound will detect the 3D discoveries in most all cases, plus more cancers beyond that, with MRI detecting even more. (Contrast-enhanced mammography is another matter, and beyond my scope here.) Nevertheless, the time has come for supplemental imaging to be routine for the high-density patient and “standard” for Level D patients, reinforced strongly with the prospective, randomized DENSE trial results – not to mention the powerful data we knew already about ultrasound screening and MRI screening from earlier non-randomized studies.

 

PS — I’ve been singing this same song for so many years it’s really sort of pitiful. But I did get all my thoughts collected in a magnum opus and published in the American Journal of Surgery recently. Here’s the pub med link to the abstract https://www.ncbi.nlm.nih.gov/pubmed/30739738 or you can write me for a copy.

 

 

 

 

 

The Plight of the Genetic Counselor in Cancer Predisposition Testing

Skolnick TIME mag

Masters prepared.  Board Certified.  Most states now declare genetic counselors as independent providers.  But billing for services?  That’s another matter.  Even though there is a code for genetic counseling, it doesn’t work well when it comes to reimbursement for the genetic counselor, and for CMS, it doesn’t work at all.  So, what is the motivation to hire a board-certified genetic counselor into an oncology program when other “providers” with little or no training will be reimbursed well in excess of the genetic counselor.  In this era where money drives everything, the answer is “there’s not much motivation at all to hire a genetic counselor.”  It’s a sad testimony that when it comes to this niche, hospitals happily endorse the “It’s Okay” mantra, a standard we see in a current TV advertising campaign.  Yes, “it’s okay” for anyone to utilize the cookbook of genetic testing (apologies to those providers who have made a concerted effort to self-educate here).

But now there is a new bill introduced in Congress to change all that.  Will it even make it out of committee?  It didn’t make it out last year when a similar bill was introduced and died.  And with the current chaos in Washington, D.C., it’s hard to imagine it will get any attention this year either.  Nevertheless, here’s an article that came out in June of this year, making the announcement about H.R. 3235… 

Genetic Counseling Medicare Payment Bill Introduced in Congress

NEW YORK (GenomeWeb) – A bill granting the US Centers for Medicare & Medicaid Services the authority to recognize certified genetic counselors as healthcare providers and reimburse them for their services was introduced in the US Congress last week.

Currently, CMS doesn’t recognize genetic counselors as healthcare providers, and H.R. 3235, the “Access to Genetic Counselor Services Act of 2019,” would require that genetic counselors be reimbursed for counseling Medicare beneficiaries in the same way these services are covered when provided by a physician.

“Certified genetic counselors are not currently recognized by CMS even though genetic counseling is a covered benefit under Medicare,” and this limits Medicare beneficiaries’ access to trained healthcare professionals who have a master’s degree in genetic counseling, the National Society of Genetic Counselors said in a statement.

The bill was sponsored by Representatives Dave Loebsack (D-IA) and Mike Kelly (R-PA), and the NSGC worked with the legislators on the bill. This issue has been a priority for the genetic counselors’ group for well over a decade, and last year the NSGC was successful in getting a bill introduced for the first time in the 115th Congress, co-sponsored by Loebsack and Representative Erik Paulsen (R-Minn.).

“CMS recognition has been a priority for our organization because the services genetic counselors provide can have a huge impact on the health of individuals and their families, especially as both the benefits of personalized medicine and complexities of genetic testing are expanding,” Amy Sturm, NSGC president, said in a statement.

The society has tried to make the case that expanding access to genetic counselors makes good economic sense for CMS and commissioned healthcare consulting firm Dobson, DaVanzo & Associates to conduct an analysis. The study, which relied on interviews, published data, and a claims analysis, projected $4 billion in potential Medicare savings over a decade if certified genetic counselors were to help patients and physicians order the right genetic tests. Moreover, when genetic counselors provide such services, they are reimbursed at 85 percent of the fee that physicians get for the same services, which could lead to potential Medicare savings of $50.7 million over a decade.

With an estimated 14 new genetic tests entering the market daily, CMS has been concerned about its growing spending in this sector and about inappropriate utilization. “Adding genetic counselors as qualified Medicare providers is an important link in achieving optimal health system performance,” Sturm said.

October – How Did Breast Cancer Awareness and Halloween Get Paired in the Same Month?

How did we end up with October as Breast Cancer Awareness Month?

Mammography schedules are jammed in October. It’s hard to work in the callbacks and biopsies. Everyone is pressured to get it done before the looming Holiday Season. And if we find cancer, it spoils that festive stretch from Thanksgiving to Christmas, Hanukkah, or whatever through New Years…not to mention the fact that deductibles were met at the time of the mammographic screening, but then in January it starts over again as cancer care continues. Ugh! How did we ever get here?

Prior to 1980, there were no pink ribbons, no races, no walks. There was very little awareness and breast cancer was not discussed in polite society. The fact that Shirley Temple Black (breast cancer in 1972), Betty Ford (1974) and Happy Rockefeller (diagnosed 2 weeks after Ford in 1974) made their diagnoses public was shocking (and trailblazing). And when the Susan Komen Foundation was established in 1982, newspapers resisted using the words “breast cancer.” As late as 1993 when we opened our doors at the University of Oklahoma Institute for Breast Health, there were complaints about our signage with its “irreverent” word BREAST plastered right there in public.

Let’s go back to the 1940s when Susan and Nancy Goodman were sisters growing up in a well-to-do Jewish family in Peoria, Illinois. Who could have conceived of the notion that both girls carried a mutation in BRCA-1 that would lead to breast cancer in the both of them? After all, it would be more than 50 years before the launch of commercial testing of BRCA-1 and BRCA-2.

susan komen and nancy brinker

Susan grew up to be the “darling of Peoria,” a beauty queen and local model. She would enter a disastrous first marriage (groom collapsed at the wedding for starters), followed by a second marriage to Stan Komen who would run a liquor store – Stan’s Wine and Spirits – in Peoria until his retirement in 2014.

At age 33, Susan felt a breast lump. Not a good thing in 1977, on the eve of a revolution about to occur in the management of breast cancer. 1977 was, however, the peak time of enthusiasm for “subcutaneous mastectomies” with the newfangled breast implants for reconstruction…sometimes patient-driven, sometimes surgeon-driven and sometimes both. Pain, cysts, “fibrocystic disease,” you name it, then cough up the money, and surgeons would perform the “scoop out” procedure with implant reconstruction. Some women were very happy with their result. Many were not. And for some, considerable amounts of breast tissue remained in place. Nevertheless, no one at the time conceived of using the procedure for treating cancer — except for Susan’s surgeon who had been recommended by her family physician in Peoria.

After performing subcutaneous mastectomy for Susan’s cancer, the surgeon pronounced her cancer-free, a tad premature since she developed positive nodes shortly thereafter and systemic metastases as well. After treatment at both the Mayo Clinic and M. D. Anderson, she was still left with chest wall recurrences and died 3 years later in 1980 at the age of 36. Given the aggressiveness of this tumor, it is hard to lay blame on the unusual subcutaneous approach used for local control, but it is noteworthy nonetheless.

Meanwhile, younger sister Nancy had moved to Dallas where she became a buyer for Neiman Marcus, and then, in 1981, she became the bride of Norman Brinker, the restaurant magnate who founded Steak and Ale, et al, (now Brinker International) and is credited with the development of that omnipresent dining staple – the salad bar. With her new financial stature and a deathbed promise to her sister Susan, Nancy Brinker founded the Susan G. Komen Breast Cancer Foundation in 1982, a mere 2 years after Susan’s death. The foundation became intimately linked to Dallas as a result of Nancy’s new home, not Susan’s home in Peoria (although Peoria did become a site for a “Komen Breast Center,” a nationwide network concept of screening centers that never happened.)

The first Race for the Cure took place in Dallas, Texas with 800 participants in 1983. The rest is history. I attended the first race in Oklahoma City (1989, as I recall) where participants ran around the racing track at Remington Park. Pink ribbons were not introduced until 1991, and though several groups lay claim to the pink revolution, I’m pretty sure it was a Komen innovation.

One year after that first Race for the Cure, Nancy Brinker was diagnosed with breast cancer. She underwent unilateral mastectomy and later contralateral prevention, even though her BRCA-1 mutation was not confirmed until 2006.

Initially, the sole agenda for Komen was to flood the country with high quality screening mammography. This drew some objections, including one prominent breast surgeon who broke ranks with the movement by clarifying that mammography is not a “cure,” and that we needed to be thinking more about a true cure and a “post-mammographic era.” Eventually, Komen expanded its scope to all types of breast cancer research.

Nevertheless, the growth of the Race for the Cure was phenomenal, taking place in a parallel fashion to the breast cancer diagnosis and treatment revolution that was well underway. It is estimated that, today, over 1.5 million participants raise money through one of several outreach programs sponsored by Susan G. Komen (several name changes of the foundation have occurred over the years, but Susan’s name is always there). Politics, of course, wormed its way into the activities of Susan G. Komen and eventually Nancy Brinker resigned as CEO.

Back to Breast Cancer Awareness in the spooky month of October. Around 1985 or 1986, the American Cancer Society teamed up with a pharmaceutical company that later became Zeneca, then AstraZeneca, announcing October as National Breast Cancer Awareness month. Zeneca was criticized for self-serving interest since they manufactured pharmaceuticals used for breast cancer. But they had, in fact, done their own internal audit on employees, showing that it was cheaper to screen with mammograms for an early diagnosis than to do nothing and pay for treatment of more advanced disease.

At this same time, the famous (or infamous) Breast Cancer Detection Demonstration Project was reporting results indicating that massive screening of the general population in the U.S. was both feasible and effective. The BCDDP was sponsored by the American Cancer Society and the National Cancer Institute, both organizations riding the waves of the War on Cancer legislation signed by President Nixon in 1971. So, by the mid-80s, the policy makers were wildly enthusiastic about general population screening with mammography, and it was a case of “full steam ahead.”

Still…why October?

I’ve not been able to nail down the definitive reason for selecting October as Breast Cancer Awareness Month, but I have a theory. Even though I can’t find the link between the rapid rise of the Susan G. Komen Foundation and the proclamation made by the American Cancer Society, I think the answer might be found by looking at Susan Goodman Komen’s birthday – she was born on October 31, 1943. She would have been 76 this coming Halloween.

 

 

 

 

Variants of Uncertain Significance – RNA to the Rescue

Nothing has plagued genetic testing for cancer predisposition more than the Variant of Uncertain Significance (VUS). After 23 years since BRCA testing became commercially available, surveys continue to reveal misinformation surrounding the VUS and/or how often the VUS is explained to patients incorrectly. Consider, too, that patients are much more likely to harbor a VUS than a pathogenic variant (a.k.a. deleterious mutation), so it’s anything but a rare occurrence.

Then, just when we thought Myriad had worked out the majority of VUS issues surrounding BRCA-1 and BRCA-2 testing, Next Generation Sequencing hit the clinic in 2013, and we were doing multi-gene panels, with VUS rates as high as 40%. “Plan on it,” we began telling our patients.

Out of frustration that clinicians were not “getting it” when it came to the VUS, word was issued from on high to simplify things – that is, consider the VUS as a “negative” result. Or, “clinically negative.” Or, more realistically: “No clinically actionable results, so don’t change your plans with the proband and don’t test unaffected relatives. And, stay tuned for updates.”

But if you do enough testing, and if you get a little too comfy with the VUS, you’ll get burned by thinking they’re all going to be negative. Yes, the vast majority of updates later on from the testing laboratory will be downgrades to benign polymorphisms, but every now and then, you’ll get an upgrade to “likely pathogenic” or “pathogenic” status.

It’s easier to dismiss the VUS when it occurs in one of those genes that barely made the A-list in the first place. When dealing with these “lesser” genes, it’s not unusual for unaffected patients to carry a higher risk for breast cancer using standard risk models than the risk imparted by “gene-positivity.”

But what about the VUS that occurs in a modest-risk or high-risk gene? This is where I rely on a genetics team that analyzes every VUS. With a medical geneticist (Marsha Pratt, MD), board-certified genetic counselor (Kate Small, MS, LCGC), and nurse practitioner (Jennifer Lee, APRN-CNP), our policy is to review the evidence for calling a variant as having uncertain significance when it involves a major gene. And what an eye-opener it is when we go to one of the various resources like ClinVar and discover that most labs call the same variant “likely pathogenic” instead of a VUS. Indeed, it is not unusual for 10 different sources to be completely split – half calling a VUS, while the other half call the same variant “likely pathogenic.” Determining whether a variant is significant or not is exceedingly complex, and it’s not only the patient who is often bewildered but also the testing lab and clinical staff.

New development – Another layer is being added to the process of working out the clinical impact of the VUS – RNA sequencing. By analyzing (post-transcription) RNA, one can more accurately separate the wheat from the chaff. More assurance will be offered that today’s VUS can be managed as a “negative” (you likely won’t know that RNA made the difference unless you read the fine print). That said, some patients currently being labeled as having a VUS will be classified as “likely pathogenic” or “pathogenic.” RNA testing works both ways – today’s VUS could be tomorrow’s deleterious mutation.

So, what about the thousands of patients we’ve tested over the years? Will we need to go back and re-test everyone who had a VUS? We did it when BART was introduced for rare rearrangements in the BRCA genes, then again with multi-gene panels, so that many of my long-term patients have undergone 3 genetic tests over the years.

As for the impact of RNA testing, we’ll need to watch for some guidelines here when it comes to those patients who completed testing in the past. It might be that only certain VUS results in the more powerful genes will need to be re-analyzed. Will we be rummaging through 23 years of records? What about those patients with a VUS that needs re-evaluation who have been lost to follow-up?

In the meantime, it is unsettling to see how many of the VUS cases are actually pathogenic upon RNA testing, after we’ve been telling patients for years that: “Your result shows a variant of uncertain significance, which is essentially negative, from a practical standpoint, that is, I mean, it could be altered in the future, but for now, well, we don’t do anything differently, and your kids or siblings do not need to be tested, so you can rest easy and just because I’m rambling doesn’t make the VUS any more suspicious than we think it is, which is, of course…essentially negative.”

Myriad Genetics has been chipping away at the VUS problem in the two BRCA genes since Day One in 1996. So, when Next Gen Sequencing (and a Supreme Court decision) opened the door to testing multiple genes in multiple labs, everyone pooled their data in order to address the VUS rate in the many genes being tested. Myriad was not so pleased about 20 years of labor being tossed out the window into the laps of their competitors, so they held their VUS cards close to the chest and did not share their massive database for BRCA1 and BRCA2. But the other labs began pooling BRCA data right away, culminating in the “BRCA Exchange,” announced January 2019 and partly funded by the NCI. The BRCA exchange is composed of information from existing databases (Breast Information Core, ClinVar, and the Leiden Open Variation Database), as well as population databases from clinicians, clinical laboratories, and researchers worldwide. At last count, the BRCA Exchange addressed 20,000 unique variants in comparison to Myriad’s claim of data on 17,000 variants. I’m not sure anyone knows to what degree there is overlap.

Despite all this refining effort, our geneticist, Dr. Marsha Pratt, presented a case a few weeks ago where a BRCA-2 VUS (confirmed as such by all sources) tracked perfectly with early-onset breast cancers and ovarian cancers in a family. Ordinarily, one would have stopped testing the family after the first affected patient tested “negative” in the form of a VUS. But Dr. Pratt was very much aware of the vagaries of labeling a VUS, so she tested another affected family member, then another and another, while at the same time, testing the older family members who had escaped a diagnosis of cancer. The so-called VUS tracked perfectly with the ovarian and early-onset breast cancer patients. After she notified the testing laboratory, this rare VUS was shifted immediately into the “pathogenic” classification, based on this one family. Ergo, the VUS problem is alive and well, 23 years after the start date for commercial testing, even in the “old” BRCA genes. Before this family came to see us, patients with this variant were called VUS and treated as “negative.” From now on, the identical variant will be called “likely pathogenic,” a world of difference.

In light of cases like this, what about the longstanding effort to train clinicians to stop over-reacting to the VUS designation, to the point that many of us can become comfortably dismissive? I don’t know the answer. All I can say is the VUS is a lurking enemy that still must be dealt with, and it’s one of the reasons I prefer working with a team of genetics specialists. (Another reason is that this team handles all tumor predispositions, not just breast cancer.) RNA sequencing won’t get rid of the VUS problem entirely, but it’s a huge step in the right direction.

POINT OF POSSIBLE INTEREST: What’s a former breast surgeon doing in this genetics space anyway? Well, the groundwork was laid when I witnessed a BRCA-positive disclosure in the research setting of linkage analysis circa 1991. I was struck by the fact that the young woman’s questions were 100% breast-related (screening, preventive mastectomies, reconstruction), and the PhD geneticist could not provide answers. I realized at that moment that genetic testing for adult-onset cancers was going to be another situation where interdisciplinary care would be critical.

Then, in 1994, two years before genetic testing began, I served as host to visiting professor Mark Skolnick, PhD who had just sequenced the BRCA-1 gene in an exciting (and controversial) race involving 12 different teams. Coverage in newspapers and magazines (TIME pic below) had generated celebrity status for Dr. Skolnick and hope for all. For all we knew at the time, the BRCA-1 gene might explain the majority of breast cancers, with or without family history (turns out, it did not).

Will Rogers -- 1995 -- Skolnick visits

During his 2-day stay in OKC, he discussed the new company he was starting called Myriad Genetics, predicting that someday testing would be so commonplace that it would be part of routine primary care. It seemed to me that clinicians were going to have to follow developments here very closely, and I was skeptical that genetic testing would become simplified to the point that it would be “just another blood test.”

At the time, I held an endowed chair at my alma mater, and I requested the formation of a task force to study the implications of genetic-based medicine. There was no response from the university hierarchy (all the way to the top), so I obtained a $100K grant from the local Presbyterian Health Foundation that allowed me to send a nurse to Fox Chase for special training as well as meeting all the requirements of excellence in genetic testing as outlined by several genetics organizations and the American Cancer Society.

When Day One came in 1996, launching this new era in medicine, I drew first blood as the only physician in Oklahoma listed on the Good Housekeeping Seal of Approval that was published by the American Cancer Society. The research geneticist, a PhD in Tulsa, was also on the list, so there were two approved sites in Oklahoma for BRCA testing. Those early years were wild and woolly (anonymous testing, high level of fear and distrust, etc.), but to watch the progress in this arena has been a rewarding experience.

It’s Hard to Get Your Gluteus Magnum Opus in Gear Sometimes

Thirty years ago, I limited my academic surgical practice to breast cancer, whereupon I made a strange observation. Granted, my experience was skewed by the referrals of younger women (with dense tissue) seeking Oklahoma’s only self-proclaimed, breast-dedicated surgeon at the time. Still, a large percentage of my newly diagnosed breast cancer patients had negative mammograms even though their tumors were palpable. At the same time, mammography was being widely promoted as having 90% sensitivity, although there was little or no distinction made as to whether the 90% applied to palpable or non-palpable cancers.

I became intrigued by the phenomenon of mammographically invisible breast cancer (few seemed to care at the time), and my first academic paper had nothing to do with surgery, but with these “invisible cancers.” (Establishing a Histologic Basis for False-Negative Mammograms. Am J Surg 1993; 166:643-647). For that paper, I reviewed the pathology of palpable, but mammographically invisible, cancers at the University of Oklahoma and found that nearly all had diffuse histology, ductal or lobular, that did not form a distinct mass. In preparing for publication of our findings, I had to write the introduction, which meant a literature search to get the ball rolling.

Unless you were publishing articles in the pre-Internet era, you can’t imagine the time it took to look up potential sources in the Index Medicus at the medical library, then manually retrieve each journal article by walking through the library, first finding the bound copies of the journal in question, then the article needed. On this particular question, I could not find the source of the oft-quoted 90% sensitivity for mammography. What appeared in my first breast cancer article was two weak references about mammographic sensitivity, just enough to get by. Many years would pass before I learned the shaky origins for the “90% sensitivity” for mammography.

But my interest was piqued. How do you know when you missed a cancer on mammography when there’s no way to double check? 12-month follow-up became the standard answer, but I found this problematic at many levels. Ultrasound was making its entrance around this time, but only to distinguish cyst from solid. Several more years would pass before benign vs. malignant became possible. MRI was still a decade away, though Dr. Steve Harms was offering audiences at nearly every breast conference an advanced look at his images obtained using his RODEO MRI.™ In case after case, he showed us pictures and narrated: “Here’s the cancer on MRI; here’s the negative mammogram.” My faith in mammographic sensitivity fell even further.

In essence, I took up a “hobby” in the form of reading everything I could about mammographic sensitivity. Over time, it became more of an obsession as I gradually put the pieces together and realized that sensitivity of screening mammography (non-palpable cancers) had been wildly overstated, most notably in women with dense breasts. At the time, few were paying attention to the dense breast issue, and my 35mm slide presentations and later Powerpoint, always included the joking reference to Rodney Dangerfield, in that breast density was simply “not getting any respect,” despite its major implications with regard to sensitivity (and secondarily, risk).

This gradual understanding of true mammographic sensitivity altered the course of my career, as I left breast surgery when breast MRI became commercially available (2003) and became a quasi-pseudo breast radiologist (“theory of…” as opposed to interpretations), focused on studying the benefits of supplemental imaging with ultrasound and/or MRI (with other methodologies in the works).

Resistance to multi-modality imaging has been powerful. And one of the primary reasons that supplemental imaging of any type is met with resistance is the false idol of mammographic sensitivity. Shortly after the introduction of MRI, Dr. Harms led CME efforts around the country, and he asked me to serve as the token surgeon where I warmed up the audience with my “90% thing,” (including Rodney Dangerfield) where I systematically destroyed the false belief that mammograms have strong sensitivity.

It’s a hard pill for radiologists to swallow, as they’ve been touting 90% for nearly 40 years. But they are caught in a bind now that we have multiple imaging methods that find double or triple the number of cancers found on mammography, rendering the 90% sensitivity for mammography impossible (except in Level A density patients). But once one admits to the deficiencies of mammography, especially in the dense breast, a whole new world of possibilities opens up with currently available imaging methods, as well as new technologies on the horizon.

So now, returning 26 years later to the same journal (Am J Surg) where I got my start on this singular question…here’s my Magnum Opus as presented via the Breast Care Network web site (where there’s another link to the actual article):

https://www.breastcarenetwork.com/news/redefining-the-sensitivity-of-screening-mammography-a-review