Sunday, 16 July 2017

#ResearchSpeak: B-cells and breast cancer

Is there a biological reason for anti-CD20 therapy to increase your risk of developing breast cancer? #ResearchSpeak

There is nothing like a 'dirty little fact' to unseat a entrenched dogma. I was at a meeting yesterday and we were discussing cancer risks and DMTs. At some point I stated that the breast cancer signal in the ocrelizumab trials may turn out to be a false positive signal. I said this as I knew of no biological reason of how ocrelizumab could cause breast cancer within a 24-36 month period. I also thought that carcinogenesis (the biological process that leads to cancer) in relation to the breast took much longer than 3 years to occur. Similarly, I made the statement based on 'immunological dogma'  that I didn't think it could be due to peripheral immune surveillance because that job is done by T-cells and NK-cells and I was not aware of B-cells playing a role. 


A very good colleague of mine from Switzerland then shot me down and quoted the paper below. In this study from the Mayo Clinic, women having biopsies for benign breast disease were followed up to see who developed breast cancer. Women with reduced B-cells in their breast tissue had an almost 6-times higher risk of developing breast cancer in the future. This data suggests that B-cells may be critical in preventing disease progression from benign to malignant breast disease. If this study can be replicated it could explain the breast cancer risk with anti-CD20 therapies and suggests a new role for B cells in peripheral tumour immuno-surveillance. The other explanation is reverse causation and that benign breast lesions that don't recruit B-cells are different biologically to those that do and the B-cells are innocent bystanders.  

I am now prepared to change my position on this topic and admit the breast cancer signal with ocrelizumab may prove to be real. However, if this is the case why should it be limited to ocrelizumab? If B-cells are necessary to keep breast cancer at bay then all B-cell depleting agents should increase the risk. 

All I can say is that we can speculate until the cows' come home; so let's wait and see what happens in the post-marketing surveillance studies. 


Degnim et al.  Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development. Clin Cancer Res. 2017 Jan 26. doi: 10.1158/1078-0432.CCR-16-2026.

Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD).


Experimental Design: A breast tissue matched case-control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells).

Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4-23.1) for subsequent breast cancer risk.

Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk.

CoI: multiple

26 comments:

  1. Oh my goodness, you just convinced me not to take ocrelizumab.

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    1. However you are not making you decision on fact.

      Maybe the Swiss guy was working for someone like Genzyme who wants you to to think alemtuzumab is safer or Merck who wants you to think cladribine is safer.

      Each drug has risks and any drug that permanently depletes your immune system is going to carry such a risk. However you have to weight the benefits and risks of not controlling ms properly.

      You can only do this with knowledge of the pros and cons.

      Maybe this is an Achilles heel for ocrelizumab. If the Swiss guy is one of the European regulators advisors then you won't get the choice to take it on not because it won't get licenced.

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    2. MouseDoc, we are struggling to trust anyone in MS care. Big Pharma is being manipulative, Team g also has its agenda.

      We're being let down.

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    3. With respect, MD, do you at Barts have no alterior motive, conflict of interest in "promoting" Ocrelizumab? I don't mean to be rude.

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    4. MD, though your comment is very illuminating, it's also very distressing. How can we trust anything any doctor says who takes money (aside from funds provided for legitimate research purposes) from the pharmaceutical companies?

      Here in the states practically every top-notch MS neuro pockets copious amounts of pharmaceutical company monies in the form of "consulting fees" and "honoraria", which have absolutely nothing to do with legitimate funding of research. In effect, this has turned most MS neuros in the US into paid spokespeople for the pharmaceutical companies. Certainly, not all toe the pharmaceutical party line, but the pharmaceutical companies wouldn't be shelling out hundreds of thousands of dollars to MS doctors if they weren't seeing a return on their investment. Some MS doctors in the US make more from pharmaceutical company payments than they do from their medical practice!

      So, how to separate the wheat from the chaff?

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    5. Do I at Barts have a conflict of interest..No not that I know of.
      I have never been sponsored from Roche/Genentech.

      ProFG on the other hand has multiple conflicts.

      The risk of cancer with ocrelizumab was something that appeared in the PPMS trials, prof G was of the opinion that it was a fluke, someone had information to pass on. Prof G relayed that information.

      Dear Wheelchair Kamikaze,

      How can we trust..,simply put they have integrity

      I think the reality is, if the neuro is not on the receiving end for their advice then the neuros may not be that good.

      The companies go to these people because they are leaders in their field and they receive recompense for their time. They get paid for giving presentations. Nice gravy train if you can get on it, however I believe that there is integrity in most neuros and if they think patient safety is being compromised they will say something


      However I will say the conflicts get lost in the massive list of potential conflicts. I think the discloses at meeting are a waste of time as they are flashed up for a nano second. They should say I am being paid to present this talk if that is the case.

      I appreciate it is a hard one to know what to trust. For me it is easy to spot the wheat from the Chaff.

      If the speaker is not presenting there own work, and it is in a company sponsored session, it is reasonable to think that are getting an honorarium to present.

      It is a easy life presenting other people data, however if they are presenting other peoples data, then buyer beware.

      If there is no real interpretation compared to simply presenting the company pitch..it is usually boring. Certain speakers are pretty dull its a bit like "Striker from Airplane the Movie". I try and think of a question to test if they understand what they are talking about:-).

      I wouldn't mind doing it.....but I couldn't answer the clinical questions

      I gave a presentation at Queen Square and the neuro said "excellent review of the literature". I was miffed every slide was original and virtually every slide was unpublished, the following week we had a neuro presenting and it "was a tour de force" according to the head neuro. There was only one original slide and that arrived at minute 55 of 60.

      Frankly when neuros regurgitate trial data I switch off but it is done for non-specialists go to hear this stuff presented by an opinion leader.

      Pharma vet all the slides for content.

      So you are correct they are often spokespeople. So aren't so are excellent, some are used-car salesmen.

      I don't know the solution but knowledge is the best way to protect against the chaff

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    6. MD, thanks for the response. Indeed, knowledge is power, but the average MS patient likely isn't even aware how much money their doctors are pocketing from Pharma.

      One of the top MS Neuros here in NYC is listed as having taken more than $500,000 over a span of 18 months in the form of honoraria and consulting fees. I understand that Genentech is doling out heaps of money to US MS neurologists in their efforts to market Ocrevus.

      Many patients will likely start Ocrevus without any understanding of the possible cancer risks or the somewhat checkered history of the drug's development, and since those risks may or may not turn out to warrant worry, many Neuros will prescribe the drug without hesitation. The medical press here has already anointed Ocrevus a miracle drug, and that's likely the only info most MS patients will know about the drug.

      As for trusting that most Neuros have integrity, your faith in human nature is much greater than mine. Seems to me that if they really had integrity they wouldn't be taking hundreds of thousands of dollars from the companies whose drugs they prescribe.

      One of the reasons my MS neuro is my MS neuro is that he doesn't even allow pharmaceutical representatives to enter his clinic. He's also not prescribing Ocrevus because of the possible cancer risks, since Rituxan is readily available and his staff is quite good at getting insurance companies to approve the drug.

      Is it possible to take tens or hundreds of thousands of dollars from an entity for whose products you are a gatekeeper and not be influenced by the money, even if only subconsciously? Again, the Pharma companies wouldn't be handing out these fees if they weren't seeing a healthy return on investment…

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  2. "All I can say is that we can speculate until the cows' come home"

    = the sorry, pitiful truth. Lots of folk need to take this drug and then we wait to see what proportion get cancer. Horrific.

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  3. So why then is Professor G is reporting this?
    To alarm people with ms?
    Does that paper was finance by Genzyme?

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  4. The link seems to point to some other paper

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    1. Fixed
      https://www.ncbi.nlm.nih.gov/pubmed/28126725

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  5. "Ïf B-cells are necessary to keep breast cancer at bay then all B-cell depleting agents should increase the risk.

    Could you tell me which DMTs are B-cell depleting and which are not?

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    1. They are all B cell depleting, some more so than others

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  6. I need a bit of help; I have been denied rituximab by my insurance- where would be the cheapest option to get this? If I were to go back to the U.K. How much would it cost to get treated privately?

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    1. I dont know the list price from the BNF.

      Delete
    2. "I have been denied rituximab by my insurance- where would be the cheapest option to get this?"

      Seems if people don't have insurance and have household income under $150,000 U.S. genentech waives the cost...not
      sure in your case since you have insurance but they are
      refusing. Read that people who had HSTC in mexico
      whose insurance refused the post-treatment rituzimab
      did get fee waivers from Genentech.

      https://www.genentech-access.com/patient.html

      Delete
  7. Did a quick search of long-term outcomes in RA patients treated with Rituxan and didn't find any mentions of an uptick in cancers.

    I'm wondering, though, if comparing Rituxamab to ocrelizumab might not be a direct comparison (certainly not as different as apples to oranges, but maybe trying to compare Macintosh apples to Golden Delicious apples).

    What I mean by this is that although Rituxamab and ocrelizumab are both eradicate CD20 cells, they do so with someone different mechanisms of action. It's possible that these differences account for ocrelizumab's higher efficacy, but may also contribute to its possibly more perilous safety profile.

    After all, the ocrelizumab RA trials had to be halted due to opportunistic infections and patient deaths, whereas Rituxan has been used successfully and safely to treat RA for 11 years now. This would seem to indicate that there is a difference in how the body reacts to these two drugs.

    This may be similar to Tysabri's dramatically higher risk of PML compared to other T cell drugs. Tysabri's mechanism of action certainly leads to this higher risk of PML when compared to drugs like Gilenya, but both keep T cells out of the CNS. So why the higher risk of PML with Tysabri?

    On a different note, Dr. G, would you be willing to be interviewed for a Wheelchair Kamikaze blog post? Would love to talk to you about therapeutic lag and its implications for treating progressive MS patients. We could do a short telephone interview (I can call you), and I can run the transcript as a blog post, thereby allowing you to explain the theory "straight from the horses mouth". We could also talk about other topics if you are so inclined. I think this would be of tremendous value to my readers, and would give your theory some wider exposure among the patient population, which it certainly deserves.

    Thanks everybody involved with this blog for all they do for the MS community…

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    1. You may be right, ocrelizumab is a more effective depletor and so people get more relatively more antibody than with rituximab, maybe this is the issue.

      Re interview may be i'm mention it when i see him in case he doesnt see your comment

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    2. Thanks, MD. I think an interview with Dr. G discussing therapeutic lag, and maybe the Charcot project (viruses and MS) would be immensely valuable. I would appreciate it if you could pass along my request…

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  8. MS is a hard enough disease, no need to throw anything else into the mix. Many of us can't afford the wait to see if the risks associated with ocrelizumab are too great.

    I resent the conflict of interest that exists in the USA with doctors and big pharma. It's difficult to believe if the DMT being prescribed is in your best interest, or in the best interest of the doctor's wallet. I'm always getting postcards in the mail of a Neuro giving a talk/meal at a local hotel regarding a DMT. Wonder if this medication is prescribed more often to get compensation?

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    1. I am sorry if I have fuelled the issue, but the recieving of cash is not just a USA problem.The difference is they are more transparent and report it.

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    2. The only reason they are more transparent about it here in The States is because they have to be. Full disclosure of pharmaceutical company payments were mandated in the Affordable Care Act (Obamacare). If the Republicans ever get their act together and repeal the ACA, I'm sure the transparency regarding doctors getting paid by Big Pharma will go with it…

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    3. Here is a search page....they disclose everything down to $13 for food/beverage

      https://projects.propublica.org/docdollars/

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  9. Likewise I was wrong to infer the person giving alternative info was simply an expert for competing interests. But there is alot of info out there and you cherry pick what you want. The earth is flat, MS is a CD4 Th17 disease. You can find data to support your case. However with time the data on which you base your current idea can be found to be true or not.

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