ER+, HER2+ - time to recurrence?

[dlaxague]

Hi all,

I'm asking a question for a chemo buddy. Over 7 years ago, we met during chemo. We had similar diagnostic details except her cancer was ERPR+. We were in the same adjuvant Herceptin trial (she got the Herceptin). We are both NED for these 7 years.

So we were talking recently and I said that I felt like (knock wood), it was unlikely that my cancer would recur this far out, given its ERPR-, HER2+ status. IOW, it was at higher risk of recurrence early-on, but now that risk was probably quite small. She said that was fine for me, but for her, being ERPR+, she still felt at high risk of recurrence. So I told her that I would ask on this forum:

For those whose primary diagnosis was ERPR+, HER2+, and node positive, and who had a distant recurrence - what is the farthest out from primary diagnosis that someone has gone before mets developed? I realize that for those who got Herceptin, it can't be much more than 7 years out (because that's about when Herceptin became available in trials for adjuvant treatment). But what about without Herceptin?

Thanks for your help.
Debbie Laxague

[Becky]

How ER+/PR+ is your friend? I think that also contributes to late recurrence rates as well as initial aggressiveness of the original tumor.

One reason (my opinion only) that highly hormone positive bc recurs later (especially if her2 negative) is that it is not so aggressive and is slow growing. In certain women, their immune systems just don't get rid of the micromets or solitary cells (and tamoxifen or an AI just keep those cells in limbo until they are off the drugs a couple of yrs). Also, one gets older as time marches on and the immune system naturally ages and gets less efficient too.

Being only ER+ and under 70%, more and more research is pointing that my tumor most likely is acting more like a hormone negative one.

I think some questions I asked of your friend's tumor can help point to how diligent she needs to be on continuing anti hormonals or not. I am just thinking out loud here. Sometimes its actually easier to do here than to say these things to your friend.

[Margerie]

Sorry I can't help with information for your buddy, but I have the same uncertainty being triple positive also. I was an across-the-board over-achiever with strong +'s for all three markers.

I have found no research that looks specifically at triple positive recurrence rates. I find lots of data comparing er/pr- her2+ with er/pr+ Her2-.

I have always wondered if one of my positives trumps the other, or if triple positive risk of recurrence lay somewhere in the middle of the two formerly mentioned groups.

Since Her2+ is so aggressive, my hunch is recurrences would tend to happen sooner versus later. And since I just hit my three year cancersucksery, I think I am going with that for now.

[Hopeful]

I am profoundly interested in this topic, as I am one of the "oddballs," with Her2+++, 80% ER+, 50% PR+ bc. I post as many articles on this topic as I can find. It seems the "highly" hormone positive, Her2+++ cases are a small subset of all Her2+++, which are a small subset of Her2+++ in general. As such, there is not much study that reflects how we will respond to treatments that address either predominantly ER+ patients OR predominantly Her2+ patients. I posted recently a correspondence between medical authorities trying to categorize tumors based on ER and Her2:

http://her2support.org/vbulletin/sho...eferrerid=1173. One of the authors suggests that ER+ Her2+ tumors are actually hybrid tumors, that are either part "luminal A" (usually ER+/Her2- with a good prognosis) or part "luminal B" (which are generally ER+/Her2- tumors with a high proliferation gene signature, a poorer prognosis than luminal A) AND part Her2+ tumor. Unfortuately, being able to categorize the tumor like that gives absolutely no information on how to treat it or how it will behave.

For ER+ tumors in general, the findings of the Early Breast Cancer Trialists' Collaborative Group at http://www.ctc.usyd.edu.au/cochrane/...BCTCGpaper.pdf state, in pertinent part:

"Extrapolation of the 15 year results for the untreated women in the Tamoxifen trials suggests that even if they had received a treatment that persistently halved their annual breast cancer mortality rate, at least a sixth of those with node-negative disease and a third of those with node positive disease would still eventually die from breast cancer during the first, second or third decade after diagnosis (in the absence of other causes of death during those decades.)"

So, while ER+ bc is seen as "more favorable" by diagnosticians than ER- bc, that seems to be a short-term way of looking at it - the risks of relapse from ER+ bc remains higher than that for ER- bc many years after dx.

Which brings us back to the original quesiton, one I asked my onc: Would ER+/PR+ Her2+ bc be more likely to recur earlier or later? He thought earlier, but I cannot imagine there are enough patients in the data base on which to base that conclusion - I think he, like everyone else, is too freaked out by the Her2+ component of the bc to really consider how the various histiological components might work together here.

My personal opinion is that triple positives carry the same long term risks as ER+/PR+ Her2- patients do, because I don't see a way to rationalize away the conclusions I quoted above from the EBCTCG just because the tumor is also Her2+. But, again, I don't know.

Thanks for raising this discussion. I look forward to other comments.

Hopeful

[kcherub]

Oh, gosh. Now, I am freaked out. I never thought of my being ER+ as a potentially "bad" thing. I know that I am younger, and thus have many more years for estrogen to pump through my body. I mean, I thought that since I have a "targeted" treatment it was better. Should I be worried that just when I get to the point where I am not worrying each and every hour that it will come back (after coming off Tamoxifen for good), that it will?

I have asked my ONC. at least five times if Tamoxifen "kills" it, or just keeps it at bay. I don't think he has ever given me a complete answer. Anyone? Or has that been answered up above?!?

I had to go off Tamoxifen last week, but only for two weeks. I have been having horrible joint pain and am being treated for two bulging discs. I wanted to see how much Tamoxifen was contributing to my pain, since everything started around the time I started Tamoxifen. Now, I am worried about the two weeks off.

Take care,

[Hopeful]

Krista,

The "good" thing about the conclusion I posted above is that more doctors and scientists are focusing on ER+ patients, and conducting tests on durations of treatment, switching between agents, etc. I am sorry that the rather stark language I quoted reads so alarmingly. I think it was intended as a challenge to researchers to try to determine which paitients require, and will respond, to extended endocrine therapy, and different types of therapy. A totally unexpected finding, reported on the Board about a month ago, was a result of giving women zolendraic acid with their endocrine therapy. Here is a link to an interview with Michael Grant from the latest issue of Breast Cancer Update with very encouraging news http://www.breastcancerupdate.com/me...08/4/gnant.asp

a portion of which is quoted below:

DR LOVE: Can you discuss the dosing schedule and results of zoledronic acid in ABCSG-12?

DR GNANT: We administered four milligrams of zoledronic acid every six months, for a total of seven infusions over three years. Initially, we started the trial with a higher dose of eight milligrams monthly, but we were forced to change due to safety concerns. In 2000, reports surfaced that renal safety was endangered in some patients with multiple myeloma who were being treated with zoledronic acid, and at that point all the trials around the world reduced the dose to four milligrams.

We went back to what we believed would be mostly a bone-protection dose. Therefore, it’s particularly striking that we are not only protecting bone at this dose but that we are also keeping the cancer at bay (Gnant 2008; [1.3]).

Two more observations are also exciting. One is the magnitude of the effect: A 36 percent improvement in disease-free survival, translating to at least a non-significant trend toward better overall survival. That’s an accomplishment usually observed with interventions such as taxane chemotherapy. We observed that efficacy with an acceptable side-effect profile (1.4).
More importantly, we’re not only preventing bone metastases, but we’re also seeing benefit in various event subcategories, including locoregional recurrence, contralateral breast cancer and distant metastasis outside of the bone (such as liver or lung disease). That’s something most of us did not expect.

So, there is promise and hope - we just need to keep on top of our own treatments.

Hopeful

[Barbara H.]

I am er, pr negative. I did not receive Herceptin in 98 and it took me 6 years to recur. I thought I was out of the woods. One can never really know the future. Try to be as healthy as possible and enjoy your break from cancer, hopefully for your life.
Hope you stay well,
Barbara H.

[dlaxague]

Hi all, great discussion. So much unknown (yet). I don't want to stop the direction this discussion is taking, as I'm sure we're all learning things as we share experience and information about what is know and what is opinion re: triple positive cancer's behavior. However, I knew that there wasn't much specific evidence to allay my friend's fears about ongoing risk because of ERPR+, so I was hoping for list-members anecdotes.

What I was hoping to get: few triple positive people writing to say that their recurrence had happened more than 7 years out from primary treatment. What's the longest anyone knows of time from primary to recurrence for a person with known HER2+, ERPR+ cancer?

My friend's ERPR was high - I think one was in the 80's and the other in the 90's. And all proliferation details were very aggressive.

I understand the points made about ERPR+ disease recurring later because it's less aggressive but that rarely if ever is a description of HER2+ cancers, right?

I got a hand-me-down ipod from our son a few weeks ago. I've just discovered podcasts. I downloaded a whole slew of breast cancer ones - bcupdate, and some that say they'll summarize ASCO - called Oncology Unplugged, from the CBCE. So fascinating, to hear the studies reported of course but even more to hear what the experts are thinking, or wondering about, as they discuss the issues in a less formal venue than a presentation at SABCS. I almost missed my exit driving home, I was so intent on the discussion of that moment, which was the very one quoted by hopeful about zometa. Another interesting one was about high-dose estrogen "resetting" the receptors so that cancer that had developed hormone resistance again respond to hormonal treatment. I think they said that there is also a study ongoing that uses intermittent AI's, same theory.

Debbie Laxague

[sassy]

My former onc (I MISS HIM) was very forward thinking and stayed on top of HER2 research. He started me on Zometa as soon as possible because he was aware of the studies possibly indicating the benefit in terms of recurrance (this was in 06), then kept me on Lupron because of emerging info about the same benefit. In terms of AI's, he felt that by the time I had been on one for 5 years, indications would be that they should be continued indefinately.

We tried to extrapolate the numbers of triple positives in the bc population and he felt that around 5 to 8% of all BC would be triple positive.

I have also been interested in any info concerning triple positives, but have not found many others in this same subset.

Considering the small percentage of triple positives and the small number of early stage who received Herceptin during the trials, I doubt there are very many in this seven+ year category.

Also, prior to the release of the trial, most people were not tested for HER2 until metastisized, so would it not be most likely that those who were triple positive that did not recurr would not have known they were HER2+?

Does this make sense?

[caya]

I don't know if this will help at all Debbie, but I am also triple positive - ER+90%, PR+50% - I was node negative. I am approaching my 2 year date of diagnosis, my 2 year cancerversary will be Dec. 18th.
Very interesting discussion. My onc.sent my tumour out for testing 3 times as the first one was inconclusive, the FISH ones were highly Her2+. He still shakes his head when he sees me, because of this very small percentage of the Her2+ population that is triple+, never mind our very small subset group in the general BC population. On top of that, my tumour was also mucinous - another very small subset (like 2%) characteristic (a favourable one, more slow growing). This mucinous aspect probably had a great deal with my tumour being a grade 2.

I am hoping that being triple+ will bode well for very, very low recurrence rates - I guess only time will tell, as we get further "out".

all the best
caya

[BethC]

Neither my breast surgeon nor my oncologist have ever given me statistics on my disease, and I haven't asked for them. However, I did ask my breast surgeon at my appointment 3 weeks ago when recurrences would most likely happen. She said that about 75% will occur within the first 2 years, and the other 25% could be any time out. So no, unfortunately, we can never really let our guard down.

[dlaxague]

I've been googling around trying to find a reference with numbers or percentages of HER2 and ERPR. I thought that HER2+ cancers were about 20-25% of all. And I thought that ERPR positive and negative were about 50/50, within the HER2+ subgroup? Which is a higher ratio of ER- than in the HER2 normal group, but it's not as if being ERPR+ and HER2+ is all that rare. In fact, it's no more rare than being HER+ and ERPR - . If memory serves, which it often does not anymore, which is why I was trying to find a reference to cite. Does anyone have that?

I knew that HER2+ cancers, if ERPR+, tended to be less positive for hormone receptors. But I saw repeatedly while chasing around that there's also apparently a relationship between LEVEL of HER2 positivity and ERPR - the higher the HER2, the lower the ERPR and of course vice versa. That's interesting.

But I still didn't find a direct answer about percent of HER2+ that is ERPR+. I did find several randomized studies that recruited all and the percent of ERPR+/HER2+ in their totals was around 12, which would fit with what I remembered (1/2 of 20 or 25).

Debbie Laxague

[Hopeful]

Debbie,

Being Her2+ and marginally ER+ (10% or less of cells staining) is not unusual. Being Her2+ and highly ER+ (80% or better) is. It is the highly triple positives that comprise that 5% of all bc stat Sassy quotes.

Hopeful

[dlaxague]

Hopeful said: Being Her2+ and marginally ER+ (10% or less of cells staining) is not unusual. Being Her2+ and highly ER+ (80% or better) is. It is the highly triple positives that comprise that 5% of all bc stat Sassy quotes.

That brings up issues. What IS negative ERPR? Lots of different answers to that question depending upon lab or provider. Research abstracts usually don't say what cut-off they used in assigning their subsets, although if you can get your hands on full text it's usually mentioned. Plus, there's the issue of unreliable assays, which I think is a larger issue than is thought, in non-central labs. (the EBCTCG overview that you posted, for example, used a cut-off of 10fmol of protein/mg of cytosol protein, or any evidence of immunohistochemical evidence of receptor protein" - how does that correlate with an Allred score, or a community lab report of "10%"? Lots of apples and oranges).

What about the research that seemed to suggest that Herceptin may make HER2+/ERPR+ disease more susceptible to hormone treatment?

Also, they were testing routinely for HER2 in 2001, even in my podunk community hospital. That was well before the release of the adjuvant trials data.

Sassy said: Also, prior to the release of the trial, most people were not tested for HER2 until metastisized, so would it not be most likely that those who were triple positive that did not recurr would not have known they were HER2+?
Does this make sense?

Yes, perfect sense. But I was not asking for those who have not recurred. I wanted to hear from ERPR/HER2+'s who did recur, more than 7 years out from diagnosis. Even if they didn't know their HER2 status at diagnosis, if they biopsied the mets, the HER2 status would be known (although a few do change from HER2- to +).

I have so many questions and thoughts on this topic that it's making my brain hurt.

Hopeful said: So, while ER+ bc is seen as "more favorable" by diagnosticians than ER- bc, that seems to be a short-term way of looking at it - the risks of relapse from ER+ bc remains higher than that for ER- bc many years after dx.

But even over the long term, there will be more recurrences in ER- cancers. Overall. Or there were, before Herceptin (there's that pesky issue again, of stats by definition being at least partly irrelevant to someone diagnosed at the time that the stats are released). When we start to try and break into smaller subsets, it gets hazier, especially, as you say, for the ERPR+/HER2+. But there should be some good subset data coming out of the adjuvant Herceptin trials on these details that we want.

Nothing's black and white, to put it mildly. I listened to more podcasts on my drive to/from work today, and several times it was mentioned that a fair amount of breast cancer overlaps categories, even in the huge gene array categories, like the other article that you noted, hopeful.

It's encouraging how much more we understand each year, but on the other hand, the incredible complexity becomes more apparent with each new understanding.

And OT to this - do people on this forum look at Adjuvant!? In one of the podcasts, they said that it will soon include HER2. This was in a discussion of whether Adjuvant! is as good as OncotypeDX, and the point made (Slamon, I think) was that when Peter Ravdin adds HER2 to the mix, it will be (as good). (and then he said "and it's free").

Great discussion,
Debbie Laxague

[Margerie]

Here is a data pool of over 61,000 women with the different subsets broken down:

http://www.asco.org/ASCO/Abstracts+%...stractID=40116

triple positives accounted for just over 11% of all primary invasive breast cancers

5 year survival was much closer in % to er+pr+her2- than er-pr-her2+ (but data from 99-04)

[sassy]

This is a great discussion.

Debbie, I'm not sure about the widespread routine testing for HER2 prior to the study release. I was DX Feb 2005 and was not tested. It was not being done at my hospital (podunk also). It was not until I had gone to a larger research facility; heard about Herceptin on the news; pointed out that I had not been tested for this, that I was tested and, sure enough, I was HER2+.

I was mistakenly thinking of those who had not recurred, rather than those who had.

Wouldn't it be nice to discover that you are not hearing from anyone who recurred 7+ years out because they haven't recurred?!

[dlaxague]

Thank you Margerie! That's very interesting. Useful for this discussion as far as percent of all cancer that is any particular subtype. And I'm surprised to see that of the HER2+'s, the larger group is ER+ (11.4% both, 3.5%ER+PR-), while the ERPR-, HER2+ group is smaller (7.2%). Doesn't that seem wrong? These are from 60K women, though, and I don't know why California wouldn't be representative. This kind of data is probably available from SEER also but I don't have time to look right now. (and again, we'd want to what the cut-off was for declaring positive or negative hormone receptor status, and what test determined this).

As for recurrence or survival, we can't learn much from this. It is for 5-year survival, pre-Herceptin. What I learn from it, personally, is another confirmation that for me (ERPR-, HER2+, no Herceptin) - my risk of recurrence was most high early-on. In addition, I note that my subgroup is at the bottom of the pack, even below triple negative by a small bit. But again, this is only at 5 years and for survival - so we don't know how many people have recurred but are still alive at this point.

And those ERPR+HER2+'s are way up there for survival at 5 years, so this hasn't answered any of the questions about longer term survival for that group. If you look hazard ratios for recurrence that contrast ER- and ER+, you see that the first peaks higher and earlier and that when they get farther out - usually around 5-6 years, they cross and the ER+ line stays more constant (although quite low) while the ER- line wanders slowly down. Same shape of graph for HER2+ vs. HER2-, although I've seen some graphs where the HER2+ line goes almost to zero after 5 years (for recurrence). But I've never seen these broken down into more detail like what we're talking about in this thread (I love graphs - for me a graph is worth a thousand words). Again, as the adjuvant data matures we should have this.

And remember - this is just a mental exercise here. This is not telling any single person what will happen with them.

And Sassy - yes, not hearing from anyone is exactly what I'd hoped to have to report back to my friend. I had no idea we'd get into such an interesting discussion.

Debbie

[Hopeful]

Margerie,

Thanks for digging up that abstract; I have it in my files but could not locate it easily.

Debbie,

Here is an abstract to an interesting article (which is only available in full for a fee) concerning the eitiology of triple positive bc: http://www.ncbi.nlm.nih.gov/pubmed/1...?dopt=Abstract

Basically, it says the older you get, the more likely you are to be ER+/PR+ and the less likely you are to be Her2+, however, they found that triple positive women were dx at a younger age than women with any other ER/PR Her2 phenotype, at a median age of 52.4 years.

They say (and I must add, these are Belgian researchers writing a paper in English, which is not their first language):

"The proportion of breast cancers beint ER+Her2+ is low, representing only 6.2% of all breast cancers in our series. . . Although our findings are hypthesis generating and awaiting to be confirmed, the reason why the small group of ER+PR+Her2+ lesions appear early in life is as yet unclear. However, our findings incorporate some of the interesting biology of Her2+ breast cancers and may shed light on the carcinogenic mechanisms for early-onset of ER+Her2+ brease cancers as opposed to ER+ Her2- cases. We suggest that high estrogen levels in young women drive ER to predominantly regulate classic ER regulated genes such as PR expression independent of Her2 whereas in postmenopausal women, low estrogen levels may allow an increasing effect of growth factor signalling on ER action resulting in a different set of ER regulated genes being expressed with a lower likelihood for PR expression. Otherwise said, at young age, Her2+ breast cancers are more likely ER+ through the presence of elevated estrogen levels whereas with aging and decreasing estrogen levels, the growth of Her2+ breast cancers is less dependent of estrogens. This is also reflected in the younger age onset of PR+ compared with PR- lesions which is mainly due to the PR+ Her2+ subgroup. The biology behind this suggests that premenopausal steriods select ER+ breast cancers to appear earlier if they are PR+Her2+ than if they are PR-Her2-, PR-Her2+ or PR+ Her2-. . . . It is well known that hormonal risk factors are different by the ER expression of breast cancer, but the drive or risk factors behind the earlier appearance of ER+Her2+ cases compared with other tumour types remains to be explored."


In my reading, it also appears that two principles are emerging: tamoxifen upregulates Her2, while herceptin upregulates ER. I think the key to long survival for triple positives is extended therapy which maintains a balance in the tension between these two opposing bc pathways. Again, I am not any type of medical professional, just what I consider to be a well read patient, and these are my opinions and no more than that.

Hopeful

[Lien]

I remember seeing a graph, a couple of years ago, that showed exactly what we are talking about.

I only remember that triple positive patients seem to do well at first, but unlike er/pr negs, the recurrences keep coming for a long time. So although they initially seem to do better, in the long run they are doing the same or even worse that er/pr negs.

Perhaps that's why my doc is leaning towards continuing AI's after 5 years?

I will try to find it later. For now I need some sleep. I spent a night at the hospital after having gone to the ER with severe stomach cramps & almost fainting. They thought it might be mets, but it turned out to be a false alarm. Its probably some pesky virus that's going round. But they didn't want to take any chances with me, so they had a look at all my internal organs. They looked wonderfully healthy. But it was a noisy night, because of a disoriented patient in the next room and I need to catch up on my sleep.

Love

Lien

[Marily]

Kristina, Hi just a quick note I had to prove I needed to get off Tamoxifin after three years. I was told this by a Dr at an ASCO meeting.. it took me a year to prove I was still producing hormone to get a Dr to do surgery to remove my ovaries. I than went to Aromasin which I was told was a safer med for me. I chose Aromasin from reading about side effects of all the AI's ... has you Dr not offered you any of these? going between the three AI 's might find you one that you can take with less side effects. for me it was a good choice. Are you still producing estrogen or are you post menapausal?
marily