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Thread: Managing cancer risks: population wide screening and individual strategies

  1. #1

    Default Managing cancer risks: population wide screening and individual strategies

    I read with interest the recent recommendations from the US Preventive Services Task Force on BRCA 1/2 testing. The tl;dr is that they were expanding the population of women who are recommended to get screening for BRCA 1/2 mutations to include more people with either ancestry or familiar history that might indicate they could have a deleterious mutation. The theory is that by targeting genetic screening at women who are most likely to be at risk, you can allow them to act before a potential cancer diagnosis: generally through enhanced and more frequent screenings or by surgical interventions to remove the risky tissue (e.g. mastectomies, oophorectomies, etc.). The early data is pretty compelling - women who acted on information found through positive screening results had significantly reduced mortality from these cancers.

    I wanted, though, to think about this on both a very high level and a very granular one. On the high level, there's a fundamental tradeoff when you get to large scale screening: Are you sure that every patient who tests positive should have an intervention to reduce their cancer risk? If you screen everyone, you might be doing more harm than good and carrying out a lot of costly, risky procedures with substantial side effects to eliminate a risk that hasn't yet turned into reality. If you only screen some people (those identified as 'high risk'), you're potentially limiting this issue, but we're still talking about a lot of women - in some populations, BRCA mutations are found in upwards of 2-3% of women, which still translates into a staggering number of potential interventions that may or may not end up being necessary. Now, it so happens that the numbers for most BRCA mutations are pretty awful - something like an 80% lifetime risk of breast cancer and a 40% lifetime risk of ovarian cancer. So the interventions might be warranted in the population. But what about cases where the evidence is more muddled? BRCA is also implicated in some other cancers (prostate, male breast cancer, IIRC pancreatic cancer) but the effects are much less stark. Should we push really aggressively to prophylactically address these cancers as well? Where do we draw the line?

    This issue is going to get trickier once population wide whole exome sequencing becomes the standard of care (probably within a decade or two). Physicians are going to be faced with mounds of data, and everyone one of their patients is going to have some number of SNPs or the like that are linked - with varying degrees of evidence - to various diseases. Sorting through which mutations (or combinations thereof) warrant an intervention, enhanced surveillance, or nothing at all is going to be a daunting task.


    On a much more granular level, the new BRCA recommendations meant that a large number of women in my social circle are now part of the recommended screening group. I've heard some really interesting upshots from their discussions on the issue and their interactions with medical professionals. Some seem to feel like they wouldn't do anything different if they received a positive result, so why bother? Others are practically planning their mastectomies before even getting the testing. So, I'll put it to you. Imagine you're given the information that you have a genetic mutation that dramatically increases the chances that you'll get a life threatening cancer in the future. Do you:

    1. Do nothing.
    2. Change lifestyle risk factors (like smoking) but do nothing else. This will reduce your risk some, but not dramatically - BRCA 1/2 are tumor suppressor genes, so any mutagen is going to be a problem.
    3. Get much more frequent screenings to catch a cancer early. This has the advantages of being noninvasive, and will reduce your risk of death substantially, but if/when you do get cancer you're still going to have to go through some pretty arduous interventions to treat it. Also, some types of cancer (e.g. breast) are way easier to screen for than others (e.g. ovarian), so your mortality risk doesn't go down as much as you'd like.
    4. Surgery, remove all of the offending tissue ASAP (or as soon as you finish childbearing). This is your best chance to reduce mortality, but it's also the most drastic with very serious side effects. There's the psychosocial aspects of removing the breasts (even with reconstruction, which has mixed results), potential side effects from removal of any lymph nodes, the early onset of menopause from removal of ovaries (with attendant implications for hormone therapy), etc. It's not fun by any stretch of the imagination. But it works really well.

    So what would you do? How do you weigh the risks against the costs of each course of action? How should thinking through this on a personal level inform how we think about recommended screening and interventions on a population scale?

    Personally I'm in favor of having as much information as possible, but I'm not really sure whether I'd opt for option 3 or 4. I'd lean towards 4 because with my background I have an unhealthy belief in the power of medical technology and interventions, but the changes this would cause to quality of life for decades are not to be ignored. Would our society be better off overall if everyone with a mutation that substantially increases cancer risk just removed the risky tissue? I'm not really sure.
    "When I meet God, I am going to ask him two questions: Why relativity? And why turbulence? I really believe he will have an answer for the first." - Werner Heisenberg (maybe)

  2. #2
    I always side with more information, as to what to actually do that's going to come down to the individual. Frequent screenings makes sense and on a larger level they seem like an appropriate thing to do anyway. Step 4 is drastic and I imagine most people would not go for it unless the chances of getting said cancer are high (and not just on a relative scale).

  3. #3
    What's high? 5%? 20? 80?
    "When I meet God, I am going to ask him two questions: Why relativity? And why turbulence? I really believe he will have an answer for the first." - Werner Heisenberg (maybe)

  4. #4
    Let sleeping tigers lie Khendraja'aro's Avatar
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    I'd probably do 3 (coupled with 2) if it's easy to screen, otherwise 4.
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  5. #5
    Under the philosophy of "do the least harm," I would imagine prophylactic surgery would not be the common choice. You don't undergo major surgical procedures and remove parts of your body because there's a CHANCE they'll be the source of a life-threatening condition sometime in the future.
    Last night as I lay in bed, looking up at the stars, I thought, “Where the hell is my ceiling?"

  6. #6
    Let sleeping tigers lie Khendraja'aro's Avatar
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    Quote Originally Posted by LittleFuzzy View Post
    Under the philosophy of "do the least harm," I would imagine prophylactic surgery would not be the common choice. You don't undergo major surgical procedures and remove parts of your body because there's a CHANCE they'll be the source of a life-threatening condition sometime in the future.
    Erm, quite literally everything is a "chance". And when the chance is approaching certainty (for example, your family has a clear and demonstrable history of this sort of thing) then you can bet your ass that everyone potentially afflicted will take a long, hard look at this.

    You seem to compare 0.01% chances with the >95% ones here.

    You also misconstrue the meaning of "least harm" - nowhere does this philosophy state that only short-term outcomes may be considered or that there must not be a weighing of alternatives. Plus, there's also the mental impact - if you have this Sword of Damocles hanging over your head that also doesn't do wonders for your health either.

    Would you also ban debridement? Or amputations due to necrosis?

    I also find it funny that you seem to think that you can quantify "harm". But please, tell one of those women who underwent a mastectomy how they were dumb for doing so. I'm sure they didn't give it a second's thought.

    Basically, this is Medical Diagnostic's trolley problem - do you let the trolley run over one person to potentially save five people? Or do you bet that the other track does not have that five people on them when the trolley passes through so you can save the one person?
    I'm quite certain that the first question of anyone confronted with this problem would be: "And what are the chances of those five people to appear on the tracks?"
    Last edited by Khendraja'aro; 09-10-2019 at 05:15 PM.
    When the stars threw down their spears
    And watered heaven with their tears:
    Did he smile his work to see?
    Did he who made the lamb make thee?

  7. #7
    Understandable but also a little funny that the task-force gave only a cursory nod to one of the most interesting ethical aspects of this issue, namely that of insurance.

    How should you reason about the pros & cons if you are--or are advising, as a family member or friend--someone who lacks adequate coverage, or is at risk of someday losing coverage?

    If you know that a woman has a BRCA1/2 mutation, without knowing anything else about her you can (with some caveats) surmise that, statistically, she may have a cumulative breast-cancer risk > 70% by age 80, with the greatest increase in risk starting already when she's in her 30s. Every year, roughly 2-3% of women like her will get breast-cancer. Whatever intervention she may choose based on that knowledge may or may not protect her from cancer, but you can be sure the screening itself may also greatly increase the likelihood of an insurance nightmare. Obviously the latter is less of a concern for a young professional belonging to a socioeconomic group where you can otherwise have a reasonable expectation of a long, healthy, prosperous and secure life with excellent coverage throughout, but, for regular people, the analysis may be less straightforward.

    It's intuitively appealing and theoretically reasonable to assume that bilateral prophylactic mastectomy will greatly reduce her risk of developing breast-cancer, but it will not eliminate it; missed tissue, ectopic tissue etc remain (marginal) concerns, esp. if screening and interventions become more routine. The best available evidence is decent and suggests there can be a substantial risk reduction, although the estimates of benefits of prophylactic surgery have to be taken with a grain of salt as they're typically calculated from comparisons against models of expected risk of cancer incidence rather than direct comparisons against eg. excellent surveillance, esp. wrt hard outcomes like mortality. The evidence is based on carriers more likely to have been selected from high risk groups, and the updated recommendations are likely to see screening applied to lower-risk carriers as well, perhaps leading to an overall reduction in benefit.

    Socioeconomic/policy issues aside, for women with a strong family history of BRCA-associated malignancies, I think an investigation is reasonable, starting with cancer genetic counseling, and including genetic testing if appropriate. Wrt interventions for people with high-risk BRCA1/2 mutations and a strong family history, even if the evidence isn't yet strong enough to confidently recommend drastic prophylactic surgery vs. other strategies, overall satisfaction tends to be high among those BRCA-mutation pos. patients with a strong family history of breast-cancer who opt for prophylactic mastectomy, and I have no grounds to dissuade anyone from that so long as there isn't more compelling evidence from direct comparisons of prophylactic surgery vs surveillance. Wrt prophylactic salpingo-oophorectomy, the jury's still out when it comes to overall benefit for pre-menopausal women in their 30s and 40s; more reasonable to recommend less drastic interventions such as the use of combined hormonal contraceptives, and compare the two strategies directly in high quality studies.

    For my part, were I to find myself in a situation analogous to high-risk BRCA1 mutation & breast cancer--with a strong family history--I would go for option 4 for the equivalent tissue. Not all tissue is created equal
    “Humanity's greatest advances are not in its discoveries, but in how those discoveries are applied to reduce inequity.”
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  8. #8
    I'm in the "do nothing" camp. Some people aren't meant to live as long as others. Why fight it? Spend your money on something that makes you happy instead of stuffing the pocket book of over-priced medical services.
    .

  9. #9
    Quote Originally Posted by Being View Post
    I'm in the "do nothing" camp. Some people aren't meant to live as long as others. Why fight it? Spend your money on something that makes you happy instead of stuffing the pocket book of over-priced medical services.
    "Some people aren't meant to live as long as others, why bother with vaccinations?"

  10. #10
    Quote Originally Posted by Lewkowski View Post
    "Some people aren't meant to live as long as others, why bother with vaccinations?"
    Vaccinations are painless and practically free. Try some chemo and you might understand.
    .

  11. #11
    Quote Originally Posted by Being View Post
    Vaccinations are painless and practically free. Try some chemo and you might understand.
    I'm just pointing out the ridiculous logic behind the do nothing camp, the idea that 'oh its better not to do something because some people shouldn't live as long as others' is bad logic. And as nightmarish as chemo is, life is typically preferred. Go ask people in remission if chemo was worth it. That said - the invasive part of Wiggin's list was surgery before tissue becomes cancerous.

  12. #12
    Quote Originally Posted by LittleFuzzy View Post
    Under the philosophy of "do the least harm," I would imagine prophylactic surgery would not be the common choice. You don't undergo major surgical procedures and remove parts of your body because there's a CHANCE they'll be the source of a life-threatening condition sometime in the future.
    Well, let's take the case I presented. An average woman in the US has about a 12% chance of developing breast cancer sometime in her lifetime. With some BRCA 1/2 mutations, that jumps up to about 80%, and the average age of diagnosis is much lower (so if you adjust not just for mortality but lifespan...). The numbers aren't quite as stark for ovarian cancer but they aren't pretty either (actually the fold increase in risk is higher, but from a lower base) - although there's some indication that BRCA-associated ovarian cancer may be somewhat easier to treat. There's not clear data yet on mortality for prophylactic tissue excision (or enhanced surveillance), but it sure looks dramatically better for this cohort.

    I think that the reason people don't want to do the surgery is just that it's a huge decision and these specific surgeries are tied up in all sorts of psychological baggage - body image, perceived sex appeal, fertility, etc. But there are lots of patients with other mutations with less psychologically fraught who do get prophylactic surgeries. The biggest example I can think of off the top of my head is patients with FAP who get prophylactic colectomies - in one of my classes in a med school I met a young patient (maybe 16?) who had elected for the surgery because of the massive risk of colon cancer. And he was carrying around an ostomy bag for the rest of his life!

    But people aren't as hung up about colons as they are about boobs and ovaries, and the data is still not as clear-cut as the benefits vs. surveillance. Even so, I think the numbers are trending that way.

    Quote Originally Posted by Being View Post
    I'm in the "do nothing" camp. Some people aren't meant to live as long as others. Why fight it? Spend your money on something that makes you happy instead of stuffing the pocket book of over-priced medical services.
    Huh, I'm really surprised at this perspective. I included it as an option just for completeness but I figured at a minimum everyone would opt for increased surveillance. This is a pretty fatalistic view - I've assumed most people on this forum were broadly optimistic about the ability of modern technology (medical or otherwise) to enhance our lives, but you seem to eschew those potential benefits. I'd really love to hear more about why you feel this way. Is it just that the additional medical care (whether testing or interventions) would be expensive, or is it something else?
    "When I meet God, I am going to ask him two questions: Why relativity? And why turbulence? I really believe he will have an answer for the first." - Werner Heisenberg (maybe)

  13. #13
    I did 15 rounds chemo and a month radiation, it took 18 months, then 3-6 months to get somewhat back to reality.
    I can't recommend it.

    I have been 'lucky' so far because my cancer is very treatable in normal situations, stats looks excellent for young adults.
    I even had a stage 4B situation with spread to bone marrow and was able to surpress it.
    (I would be very careful with the word cure :P)

    I know I might get it back a year from now or 10 year from now... maybe more likely, something else.
    I usually concider Paul Allen's fight to be a possible future if I'm lucky.
    I hope medical science will have advanced a bit by then. (30+ years).

    So given uncertainly, if possible always get rid of the crap (4).
    Mine isn't possible to 'cut' and it's an apple to pear comparision.
    To my understanding, some growts can create bi-effects such as hormone disturbances too etc. even if not directly dangerous...

  14. #14
    Quote Originally Posted by wiggin View Post
    Well, let's take the case I presented. An average woman in the US has about a 12% chance of developing breast cancer sometime in her lifetime. With some BRCA 1/2 mutations, that jumps up to about 80%, and the average age of diagnosis is much lower (so if you adjust not just for mortality but lifespan...). The numbers aren't quite as stark for ovarian cancer but they aren't pretty either (actually the fold increase in risk is higher, but from a lower base) - although there's some indication that BRCA-associated ovarian cancer may be somewhat easier to treat. There's not clear data yet on mortality for prophylactic tissue excision (or enhanced surveillance), but it sure looks dramatically better for this cohort.

    I think that the reason people don't want to do the surgery is just that it's a huge decision and these specific surgeries are tied up in all sorts of psychological baggage - body image, perceived sex appeal, fertility, etc. But there are lots of patients with other mutations with less psychologically fraught who do get prophylactic surgeries. The biggest example I can think of off the top of my head is patients with FAP who get prophylactic colectomies - in one of my classes in a med school I met a young patient (maybe 16?) who had elected for the surgery because of the massive risk of colon cancer. And he was carrying around an ostomy bag for the rest of his life!

    But people aren't as hung up about colons as they are about boobs and ovaries, and the data is still not as clear-cut as the benefits vs. surveillance. Even so, I think the numbers are trending that way.
    The specific probabilities matter too. You say with some of the mutations, the probabilities jump to 80% over a lifetime. Aimless cited some slightly different numbers, ~70% by age 80 (presumably for the BRCA mutations overall). The estimates I found before writing my post were 55-65% by age 70. I'm perfectly willing to acknowledge that as the estimated probability grows, the more reasonable prophylactic intervention seems. Where the line is or should be does not seem like something we can reasonable quantify (and will be changing over time as developments in screening or hopefully someday even effective treatment change). And as you say, not all tissues are created equal, some are physiologically or psychologically more important than others. Maybe a women with a high risk of ovarian cancer will plan on having them removed, but only after procreating. Another might not be interested in procreating at all and spreading the mutated gene around.
    Last night as I lay in bed, looking up at the stars, I thought, “Where the hell is my ceiling?"

  15. #15
    Quote Originally Posted by LittleFuzzy View Post
    The specific probabilities matter too. You say with some of the mutations, the probabilities jump to 80% over a lifetime. Aimless cited some slightly different numbers, ~70% by age 80 (presumably for the BRCA mutations overall). The estimates I found before writing my post were 55-65% by age 70. I'm perfectly willing to acknowledge that as the estimated probability grows, the more reasonable prophylactic intervention seems. Where the line is or should be does not seem like something we can reasonable quantify (and will be changing over time as developments in screening or hopefully someday even effective treatment change). And as you say, not all tissues are created equal, some are physiologically or psychologically more important than others. Maybe a women with a high risk of ovarian cancer will plan on having them removed, but only after procreating. Another might not be interested in procreating at all and spreading the mutated gene around.
    Agreed that the numbers and the counterfactuals matter, and that the calculation is going to differ for each individual. I guess what I'm trying to get at is less a definitive answer and more of a discussion of how you weigh those risks, and how we should pursue this from a public health perspective.

    More broadly, we're getting to the point where we're going to have huge amounts of data that correlate someone's genetics or lifestyle with later health problems, all with reasonably accurate probabilities thrown in. And we're also getting to the point that there's somethings we can theoretically do about it prophylactically, though the options aren't always pretty. I'd really like to understand how society is going to grapple with deploying healthcare resources to address these issues.
    "When I meet God, I am going to ask him two questions: Why relativity? And why turbulence? I really believe he will have an answer for the first." - Werner Heisenberg (maybe)

  16. #16
    At the policy level:

    1) We already fail at early cancer detection/screening, in large part because medical care is tied to Health Insurance. We can't even be assured that pre-existing conditions will be protected under the Patient Protection part of the ACA, let alone genetic mutations. That makes mass-scale genetic screening sound impractical and even ridiculous.

    2) Genetic screening can easily done on newborns, just as their cord blood/stem cells can be used in medical research. (Parental consent is often hidden in the hospital contract fine print.) I'm concerned that managing risks could begin at birth, giving genetics a primacy that could be dangerous. It reminds me of eugenics.

    On a personal level:

    1) I have a family history of breast cancer on my father's side. My mother was adopted. I had benign breast cysts surgically removed...which meant I couldn't get Insurance that covered any breast tissue. I had benign tumors removed during C-sections births....so I couldn't get Insurance for anything related to ovaries or uterus. Basically, none of my female anatomy could be covered by Insurance, as it all fell under "pre-existing conditions" <higher risk> that Insurers could deny.

    2) My income precludes Medicaid, my age precludes Medicare, and I don't have an Employee Group policy. Millions of people share my predicament; paying OOP costs for things like mammograms, ultrasounds, pelvic exams or even PAP smears means we don't do them as often as recommended. (And who can keep up that anyway, since it changes every few years?) Why would I want a blood test under these circumstances?

    wiggin, I'm glad we have medical academics like you, pushing science forward. But putting the cart before the horse never works.

  17. #17
    btw, it's pretty hard to convince people that cancer is their biggest enemy, when opioid addictions and/or gun deaths is a more immediate threat.

  18. #18
    Quote Originally Posted by LittleFuzzy View Post
    snip

    Maybe a women with a high risk of ovarian cancer will plan on having them removed, but only after procreating. Another might not be interested in procreating at all and spreading the mutated gene around.
    And maybe ovarian cancer is a virus spread by men carrying a certain gene.

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