Ladies on Tamoxifen -- What do you think about this research?

Lisa123456

I found this research a while ago, but didn't want to bring it up because it was so unorthodox:

Tamoxifen promotes invasion of E-cadherin deficient MCF-7 cells

Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells

What do you, ladies, think? Am I understanding this correctly, that TAM can trigger BC in someone with LCIS/ALH ?

leaf

I think its too early to make a judgement, especially based on one paper. (I don't have time to see if there are other papers that have said the same thing.) I don't have time to research now, but I'd want more research. Since its quite unlikely to find a study that actually looks at the outcome of LCIS/ALH women treated with tamoxifen - that study would probably take decades -, is there a study that follows ILC and says that ILC women do more poorly with tam than without tam?

I would first want this study to be replicated, then look at outcomes. Sometimes strategies that 'make sense' on a theoretical level do not have the same outcome in the real world. Sometimes two meds that have the same mechanism of action produce different outcomes, even though we would have guessed beforehand they would have equal efficacy.

Some conditions are much more complex than we guess. We don't know what factor in LCIS/ALH puts us at higher breast cancer risk.

This may very well be a true finding, but I wouldn't want to change therapy based on one paper.

Its certainly a very interesting finding, and I hope they follow up this paper more. Thanks for sharing and posing this question!

Lisa123456

Thanks for responding, Leaf. I, actually, found two studies on the subject (see 2 links in my original post).

WRT a study done on women with ILC, I can't imaging how that would be possible since they don't walk around with their e-cadherin-deficient cells. These cells are gone as soon as discovered, and then the patient might be put on TAM. I think we are the only cohort of patients to whom this research is applicable in real life.

If I just had access to a good oncologist, I'd love to discuss these papers with him/her. Unfortunately, I'm being followed by a physician who works at my local breast center and specializes on benign breast diseases. Anything I bring up, she takes as "you don't trust us".

leaf

I was thinking that ILC is sometimes/often diffuse, and some unfortunate people have ILC mets on diagnosis, which are often not removable. You're right, I didn't clarify that. My bad.

Well, in this large 2015 study (1,032 LCIS women undergoing surveillance), LCIS women on chemoprevention did better than those that did not. (See Fig 2B)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC49346... There were 173 LCIS women who did chemoprevention without BPMs, and of these, 10 women developed 13 cancers.

Breast cancer incidence was significantly reduced in women taking chemoprevention (10-year cumulative risk: 7% with chemoprevention; 21% with no chemoprevention; P < .001). In multivariable analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50). In a subgroup nested case-control analysis, volume of disease, which was defined as the ratio of slides with LCIS to total number of slides reviewed, was also associated with breast cancer development (P = .008)patients cancer free by chemoprevention (CP) use (n = 175 with CP; n = 857 without CP);

On multivariable analysis, including age, mammographic density, chemoprevention use, and family history of breast cancer, only chemoprevention use was significantly associated with breast cancer risk reduction (hazard ratio, 0.27; 95% CI, 0.15 to 0.50; P ≤ .001; Table 3). (emphasis mine) Obviously, this does NOT include PBMs.

They also refer to other studies that show chemoprevention did reduce risk in LCIS women, although the number of LCIS women in the NSABP P-1 trial was small:Chemoprevention with a selective estrogen receptor modulator or an aromatase inhibitor reduces breast cancer risk by 40% to 65% in women at elevated risk,^22–25 and data from the NSABP P-1 trial suggest that women with LCIS derive even greater benefit.^24,25

In this paper, for those women considering PBMs, Thirty-two women opting for bilateral prophylactic mastectomy are still in active follow-up with a median follow-up time of 68 months (range, 22 to 237 months); all remain cancer free. (emphasis mine)

Of course, with chemoprevention AND PBMs, there are significant risks, so, if you choose one of them, you get to pick your poison. (Chemoprevention can put you at higher risk of blood clots, uterine cancers, cataracts, etc; PBMs put you at higher risk of lymphedema, chronic pain, mobility issues, and (if reconstruction is desired) unsatisfactory appearance. I'm sure I didn't list all the risks.

We don't understand what exactly puts LCIS women at risk, but there may be more than one factor: Within this LCIS cohort, 63%, 25%, and 12% of subsequent cancers were ipsilateral to the breast with LCIS, contralateral, and bilateral, respectively. This finding and molecular evidence demonstrating that gene expression can distinguish two LCIS subclasses,³⁰ that approximately 70% of LCIS lesions seem to be clonally related to synchronously diagnosed invasive lesions by copy number analysis,³¹ and the frequency of common mutations in microdissected LCIS and infiltrating lobular carcinoma³² suggest that LCIS is a heterogenous lesion representing both a nonobligate precursor lesion and a high-risk marker.

Tissue culture can be very, very different than actual women. But still, the papers you cite are interesting. Thank you again for posting them.

NicolaSue

So to ask potentially a dumb question (and if I do, very sorry) - does the research currently indicate that LCIS is an early breast cancer (ie stage pre zero) or simply an indicator of increased risk in the future.

If it is actually considered a pre pre zero cancer then that doesn't tally with the conservative management here in the UK where you don't usually surgically remove LCIS and if it's only LCIS that's found it's usually left alone.

leaf

No question is dumb - and that goes double or triple with LCIS. Almost everything about LCIS (including the name) is controversial.

(Classic) LCIS was first described in 1941 by two pathologists, Foote and Stewart, by looking at breast tissue slides. (DCIS was first described in roughly the 1890s.) Foote and Stewart did NOT know the natural history of LCIS - in other words, they didn't know what happened to untreated LCIS women. They thought LCIS was analogous to DCIS. If untreated, DCIS will turn into IDC. Foote and Stewart thought LCIS was like DCIS, that everyone with LCIS would eventually get ILC, so they recommended bilateral mastectomies. They didn't know that, at least for classic LCIS, that the majority of LCIS women would NEVER go on to get DCIS or invasive breast cancer. They stopped routinely doing prophylactic bilateral mastectomies for LCIS in roughly the 1990s. It was the 1990s that pathologists also first described atypical LCIS such as pleomorphic LCIS (which is more unusual than classic LCIS.)

Usually cancer is described as uncontrolled growth of cells - in other words, the cells just keep on growing and growing. But some people have other definitions.

The anatomy of the breast is that there is a complex system of ducts and lobules which end up in the nipple, but it is thought that the ducts don't intersect. (One pathologist painstakingly injected wax into a cadaver's breast and dissolved away the tissue, showing the complex anatomy of the ducts.) I don't think they know if the lobules are/could be connected to each other, but I may be wrong about this.

This might be analogous to the streets of a town that lead to a freeway (the nipple). But this is a strange town: in this town there are NO intersections. All of the streets are lined with sidewalks (which in the breast would be the basement membrane.) Non-invasive cancer is when the cancers are restricted to the street pavement: they do NOT ever cross the sidewalks into the houses or the backyards. Invasive cancers are when the cancers cross the sidewalks (the basement membrane) into the rest of the breast tissue (the stroma). Invasive cancers then have the potential of traveling to the lymph nodes, and from there anywhere in the body (metastasizing).

Of course, you cannot see cells growing in a microscopic slide. The cells in a microscopic slide are dead: they have been killed and stained and thinly sliced so light can pass through them so we can look at them in a microscope. You can estimate how many cells are trying to divide though (are undergoing mitosis.) There are cells that look totally normal, and other cells that look totally cancerous (beast up and irregular). There is also a continuum of cells between the two: there are cells that look somewhat normal and somewhat cancerous. That's why you need pathologists. Some pathologists disagree on what is LCIS and what is ALH, and disagreement on a lot of other things.

DCIS is mainly in the ducts, and LCIS is mainly in the lobules. Since both DCIS and LCIS do NOT cross the basement membrane (the sidewalk), they are NOT invasive breast cancers. In a literal sense, they are NOT uncontrollably dividing because they are held by the basement membrane. If they kept on growing, they would break/pass through the basement membrane, and thus become invasive cancer.

Some members here with LCIS and nothing worse (in other words, no DCIS or invasive breast cancer) have been told by their doctor they they DO have cancer. But I think MOST if not all doctors now believe LCIS is NOT a cancer.

Its really hard to study LCIS because we can't RELIABLY tell that a tissue is LCIS without looking at it under the microscope. In order to do that, you obviously have to remove the tissue from the breast, so you can't study the LCIS tissue growing undisturbed in the breast over time. We have no idea how many women are walking around with LCIS and don't know it because they've never had a breast biopsy.

___

So I'm not sure what 'pre-cancer' is and what 'pre-pre-cancer' is.

To partly answer your question, its not POSSIBLE to RELIABLY 'remove all LCIS from a breast' without doing a mastectomy. Even with a mastectomy, you inevitably leave some breast tissue behind. They know that LCIS is almost always multifocal and usually bilateral, because between 1941, when LCIS was first described, and roughly 1990, most LCIS women got bilateral mastectomies, and they could sample the mastectomy specimens. There is NOT a way to reliably know if any particular area of the breast has LCIS without biopsying it.

When I first got diagnosed with LCIS in 2005, they thought that LCIS was 'just' a marker for higher risk for breast cancer'. Now, according to this 2015 paper, they think it may be a more complex scenario (although of course as with almost everything in LCIS there is controversy.) They think that approximately 70% of LCIS lesions seem to be clonally related to synchronously diagnosed invasive lesions by copy number analysis,³¹ and the frequency of common mutations in microdissected LCIS and infiltrating lobular carcinoma³² suggest that LCIS is a heterogenous lesion representing both a nonobligate precursor lesion and a high-risk marker.

This means that these authors think that about 70% of LCIS lesions have genetic mutations in common with ILC. If I understand this correctly, this means that some LCIS lesions have the mutations of an invasive lobular cancer, but may or may not grow slowly enough to become an ILC, and that some LCIS lesions just have 'something unknown' that puts the breast at risk for DCIS and invasive breast cancer. Most (over 50%) LCIS women who do go on to get invasive breast cancer do get IDC, but the incidence of ILC is higher than in the general female population (without known LCIS).

But still, at least with classic LCIS and no other risk factors such as a known deleterious BRCA mutation, probably less than half of classic LCIS women will EVER go on to get DCIS or invasive breast cancer in their lifetimes.

Hope this helps.

NicolaSue

Leaf, this is hugely helpful thank you very much indeed!

I noticed you were diagnosed on 8 Dec some years back. That's my birthday!

I am going to re read your post several times as it's so helpful.

Lisa123456

I'm struggling with the decision I made a year ago to start on TAM. Not because of the side effects, which so far are limited to hot flashes, but because I keep coming across information that TAM might not only be useless, but harmful. I think I'm menopausal (I'll ask for a test to confirm it though), so wouldn't it be much better for me to switch to Arimidex?

Here's a research paper that seems to point to an almost complete ineffectiveness of TAM for patients with LCIS: Impact of preventive therapy on the risk of breast cancer among women with benign breast disease

I'd appreciate your thoughts, ladies.

leaf

In the paper you cite, there were 13 (tamoxifen) or 12 (Placebo) LCIS women who got breast cancer, each in a group of 44. So there is no significant difference between tamoxifen and placebo in this group.

In the study I cited, there were 10 women who developed 13 breast cancers out of 173 women who took chemoprevention (which may or may not have been tamoxifen) for varying lengths of time. In the surveillance group, about 140 (150 total - 10 from the chemoprevention group) out of 831 women got breast cancers. (About twice as many.) This study has more patients, so perhaps a more powerful study.

All of these groups are rather small actually. In the study I cited, if you could glean out the groups that actually ONLY took tamoxifen for 5 years and the women who ONLY had LCIS, maybe the study I cited COULD have had just as small numbers as your study. (In the study I cite, the chemoprevention group had more risk factors than the surveillance group, so the net effect might be greater than studied.)

So we surely need more studies. The numbers are too small. But it just takes LOTS of time to study an unusual condition like LCIS, which is very difficult to study because it can only be reliably diagnosed by a biopsy.

But I don't know of ANY papers that show that chemoprevention groups get significantly MORE breast cancers than placebo groups. Of course, this might happen by chance, or if the placebo and chemoprevention groups were not equally matched, or other things I don't know. I haven't looked at every LCIS paper out there either.

So the study you cited 'disagrees' with the study I cited. So, you make hypotheses. Why was 'your' study different from 'my' study? Maybe they took women with different characteristics. Maybe they measured things differently, or defined 'LCIS' differently. Lots of things I don't know.

The vast majority of LCIS papers I've seen use <100 people in each group. (They may combine several groups together and get hundreds or thousands of people in a group, but if you take specifics, it quickly gets small. For example, even if you have 44 LCIS women in a surveillance group and 44 LCIS women getting chemoprevention, maybe the chemoprevention people took chemoprevention for different lengths of time, or maybe they were of different ages when they were diagnosed with LCIS or took chemoprevention. If 80% of the placebo group are PREmenopausal and 80% of the chemoprevention group are POSTmenopausal, you are not comparing chemoprevention vs placebo well - you are not designing the study well.)

Different studies will look at slightly different questions in different ways with different groups. Nobody comes to 'the truth', because there isn't a 'final truth'. With the scientific method, scientists keep on arguing between themselves, looking at problems in different ways, always curious. Some scientists cling very tightly to hypotheses they propose, some are more self-critical, but science is self critical, and eventually things closer to the truth, with more nuances, will come out. It may take lots of time, and you have to give scientists the freedom to come to their own conclusions, without fear of reprimand of some sort. We thought Newtonian physics was all there was to say about physics until Einstein came along. Then Einstein found more nuances, and, 100 years later, we still have lots of holes in our physics theories.

NicolaSue

Even if sample sizes in studies are big enough for the results to have 'statistical significant' (ie be valid) there will always be another valid study with a different finding.

For me it's been a difficult decision. Using plain English, the choice is stick with LCIS only knowing that possibly something else is brewing not today but in 5 10 15 years time so have lots of surveillance in the meantime. Or, take chemoprevention which does appear to have evidence showing that it does some good. It also does some harm.

Now an oncologist would likely tell me (has told me!) to go ahead with chemoprevention. But he's an oncologist and I also have another complex condition - had my thyroid removed for borderline thyroid cancer (some centres said it was malignant, some said not). So I take thyroxine to replace the lost thyroid. Thyroxine appears to be extremely sensitive. I can eat some foods and the thyroxine doesn't work the same way in the body. I can exercise for a bit more than usual...same thing. How thyroxine works in my body is constantly changing. So in my specific case do I want to add in a chemoprevention drug when I'm struggling as it is. Nope! If I had invasive cancer would I....well yes that would be very different and the evidence is overwhelming that full blown treatment is justified. But in my particular circumstances I've decided I don't see sufficient evidence to make it worthwhile taking. But the point I'm making is that we are each of us in different circumstances and doctors don't always understand those circumstances so....the decisions are hard.

Lisa123456

I don't think I made myself clear: I'm not against chemoprevention. Au contraire, I'm all for it. I'm just not sure that TAM is the right type for someone like me, and the study I linked to seems to say that AI would be a much better choice. Here's the excerpt:

For women with LCIS at entry, no difference between tamoxifen and placebo was observed (HR = 1.05 (0.48–2.30)). For those with AH, a reduction of 56% was noted for women receiving tamoxifen compared to those on placebo, but the numbers were small and the difference was not significant.

Breast cancer incidence was reduced by 74% with anastrozole for women with LCIS at entry (HR = 0.26 (0.06–1.24)) and a slightly smaller effect was seen for women with AH at entry (HR = 0.35 (0.12–1.07)), which was still larger than that for other women in the trial.

leaf

Thank you, Lisa, for clarifying. I sometimes have a LOT of trouble listening to people: I'm just not focusing well enough on what they say. My apologies.

I think its also interesting in the https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46365... paper, the tamoxifen worked better for the AH than the LCIS. SInce some/many pathologists lump ALH and LCIS into the category of lobular neoplasia, was there problems in this (and all ALH/LCIS papers) about categorization? In other words, were patients with the same degree of neoplasia were classified together, since they were diagnosed by different pathologists?) If it is a 'true' result, why would TAM work better for AH than LCIS? Maybe the AH people included ADH people and TAM worked better for ADH people?

Obviously, premenopausal women can't use an AI. So some women can't use an AI.

By bringing up the raw numbers, you can see that most LCIS groups are less than a couple of dozen people, so its really hard to reach statistical significance. As NicolaSue says, that makes the decision harder.

BTW, to reinforce we are ALL individual, I also take levothyroxine because a thyroid adenoma (half of my thyroid) was removed. (I am NOT trying to invalidate NicolaSue's experience!) In my case, in wasn't malignant. But I've had no where near as much problem with thyroid levels as you. But a colleague who had Grave's disease had a Horrible time adjusting her thyroid levels. We're all so individual! I'm so sorry you are both going through this, especially Lisa and NicolaSue!

KJWLAM

Hello Ladies ❤️

I just finished active treatment at the end of February 2017 for IDC Grade 3 ER+ Her2 negative, I came across this page which helps to put things into perspective with regards to reading about absolute benefits of treatment when comparing two treatments etc. students4bestevidence.net/statistical-significance-vs-clinical-significance. My Onc keeps on pushing the relative benefits of treatment as opposed to the absolute benefits and almost feel like he's patronising. Really feel like he is reading from a script sometimes and tries to fob me off, never get a strate answer 😔) ....integrativeoncology-essentials.com/2016/03/the-most-important-statistic-you-need-to-know/ I'm really struggling with the whole recurrence side of things, I've found the psychological impact of BC harder than the treatment itself.

Best wishes to you all!

Emma x

leaf

How frustrating!

I've had some of my health care providers do a similar thing. It wasn't until my GP implied they really didn't know who would go on to get breast cancer, that I found this https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djj501, which is for the AVERAGE woman in the USA, not with LCIS or DCIS or invasive breast cancer. The science of prediction about breast cancer (or its treatments) is in its infancy.

Hipline

There is a webinar tomorrow with researcher Steffi Oesterreich and clinician Rachel Jankowitz on ILC and you can ask questions at the end. Here is the link. Webinar is sponsored by ABCD where I am a mentor. Thanks.

http://hosted.verticalresponse.com/1808367/3978e23d8c/TEST/TEST/

beach2beach

Initially I was diagnosed with IDC on biopsy. On pathology after mastectomy it was changed to ILC/LCIS and DCIS all within the same 7mm tumor/tissue. Chicken or the egg. That was one busy tumor, and ILC won out in the end.

Gardengirl72

Hi Ladies,

So I read this and all replies and it just seems so uncertain and vague. I was not only diagnosed with LNIS (I choose to use neoplasia as it’s not a true carcinoma) but AH. So what do you do about the conflicting reports that it helps AH and not so much LNIS. I read soooooooo many studies, studies I found and studies my breast surgeon printed out for me. I was on TAM for almost 2 years and I am premenopausal at 45. I went off it 3 months ago (haven’t told my Drs yet) because of crushing joint pain (I felt like I was 80’s old and couldn’t get a decent nights sleep). This has finally resolved after 3 months off. I do take iodine and there’s are many emerging studies that show its is similar if not better tha TAM. Everyone makes their own decisions. I’m just scare of making the wrong one. Glad I have these boards.

Xo

Lisa123456

I pulled the plug on TAM yesterday, after 1 year of taking it. Since I'm now officially menopausal, I asked my doctor for an Arimidex prescription. My intention is to take it for the next several years regardless of side effects. I'm just not sure how soon I should start taking it after discontinuing TAM. I read that TAM effect lasts a long time.

Hi-Risk-4BC

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