Understanding the impact of HER2 on progosis/survival

BlueFox

I'm a bit of a geek and I've been playing around with one of the online risk calculators http://www.predict.nhs.uk/ in order to get a better understanding of the impact of Herceptin for those of us with HER2 positive cancers.

I appreciate this thread may not be of interest to everyone - some people are not comfortable thinking about the numbers and others are not as geeky as me, but perhaps a few will find it o interest. I'm a layperson so this is no substitute for discussions with your onc.

The predict tool was developed using a fairly large dataset (over 5,000 cases) and validated using other datasets. Unlike other online tools such Adjuvant and CancerMath, it includes the impact of Herceptin.

According to the Information for Professionals section, the benefit of Herceptin is based on a relative risk reduction of 0.31 up to 5 years. I've read some studies give a higher risk reduction up to 0.45, and some show a benefit further out than 5 years. This implies that they are using estimates at the cautious end and the actual benefit could be higher than the tool shows.If you plug in your own numbers you will probably see that the benefit of Herceptin is much lower than that of Chemo (and Hormone therapy where appropriate), but it is still significant in increasing survival.

If you try switching the HER2 positive input to HER2 negative, you can see how your prognosis compares with that of someone whose cancer was similar except for the HER2 effect. In most case, once you include the benefits of Herceptin, the survival chances are similar but slightly lower. But given they've been cautious in estimating the Herceptin benefits, it may be that your prognosis is actually a bit better than someone with a similar cancer but HER2 negative. Either way the survival is broadly similar.

I was initially surprised that impact of HER2 positive on survival wasn't greater given we read about how much more aggressive these cancers are.

I think I've figured this out as well. Have a look Figure 4 in this paper http://www.biomedcentral.com/1756-0500/5/376 . This shows that most hormone positive/HER negative (luminal A) are lower grade but most most HER positive cancers are higher grade.

The Predict tool results show that for a given grade, HER2 positive doesn't make much difference to survival, once the impact of Herceptin is included, everything else being equal.

But if you try playing around with the grade switch, you will find that grade is quite important and the fact that HER2 cancers are mostly (but not always) higher grade probably explains what we read about their aggressiveness.

BlueFox

Thank you for these appreciative comments.

Geeks rule! Knowledge is Power!

Yes, I find numbers/information reassuring - in the absence of data I tend to just assume the worst and it is usually not as bad as that. Online calculators are much better than old statistics because they include the effects of modern treatments, which are often lacking in raw data (often out of date anyway).

Interestingly, all online risk calculators seem to show that the most beneficial treatment after surgery is chemo (for the riskier cancers anyway).

The calculated effect of Herceptin assumes people are already doing surgery, chemo (and hormone therapy where appropriate) as Herceptin is rarely given without chemo and therefore there is no data on Herceptin only. But given chemo gives such a big benefit (for riskier cancers anyway), I can see why they never just want to give Herceptin. If your cancer is risky enough to need Herceptin, it is too risky to skip chemo (unpleasant though it is).

BlueFox

You are quite right.

What I meant was, that was the rationale/logic behind Herceptin only being given with Chemo in early cancer.

BlueFox

Interestingly, trials have been undertaken which show promising results for the use of two anti-HER2 drugs (dual blockade). In future some HER2+ patients may be able to safely skip chemo, but more results are needed to identify the appropriate cancer types.

See: http://jco.ascopubs.org/content/31/14/1703.full.pdf

BlueFox

I've read in a couple of papers that pCR is not predictive in luminal HER2 positive (ie hormone positive, HER2+) but it is predictive in nonluminal HER2 positive (ie hormone negative).

dancermom

I did not have pCR, although I did have a very good response, went from a 7 cm tumor to 2 mm. I am triple positive, so am really interested in what you said. Also my very unscientific study of the stage 4 ladies here seem to indicate that more are her2 negative or if her2 positive, did not have herceptin originally or were diagnosed stage 4 from the start much more often than the Her 2 neg patients. I think herceptin really is a miracle drug.

BlueFox

That was my thinking as well.

I started the Anastrozole after radiotherapy and therefore I will be having Herceptin and Anastrozole at the same time for around 6 months, and this may produce a dual blockade affect.

Why not ask your onc whether your cancer belongs in the Luminal B group (HER2 subgroup) or in the HER2 group?

AlaskaAngel

Bluefox, thanks for the interesting discussion. I have a question involving this statement you made:

"Interestingly, all online risk calculators seem to show that the most beneficial treatment after surgery is chemo (for the riskier cancers anyway)."

The problem I see with that is that if one applies unbiased equal scientific analysis to any ingredient of treatment, that analysis has to be just as rigorous in evaluating chemotherapy as a component. Unfortunately, because chemotherapy has been used as the standard against which any new treatment is measured, we don't have an accurate measure of how effective it is. If chemotherapy were receiving equally rigorous evaluation as other components of treatment, the question of what percentage of patients do worse due to the addition of chemotherapy as a treatment component would be evaluated and counted as part of the prediction. The predictors do not include any calculation for that possibility, which favors chemo over other treatment components.

Another example of the bias favoring chemotherapy that I raised in another discussion about it recently on one of the forums is that the predictors ask no questions about and do not include any measure of benefit for doing radiation, yet presumably radiation IS of some measurable benefit to the patients who receive it. If those benefits are not calculated as part of the total benefit, then the benefit of other therapies such as chemotherapy would be again, overestimated.

Is that not reasonably correct?

 

annika12

Hi,  I am also a low 3%er and my oncologist wants me to at leased try hormonal treatment my surgeon agrees !! I had chemo before surgery and I think it made me interesting to my docs. I dont have my path report in my hand yet but all that was left after 4AC 12 taxol and 12 herceptin treatments in 2 3cm lymph nodes tumors were 2 isolated tumor cells !!!  My doc called me cancer free  I will ofcourse continue my herceptin for a full 52 week treatment and most likely also have radiation      

Gracers55

Kayb and Annika

Glad I found this thread. I'm in the Unsatisfying position of being only 1% ER+ and PR-. I'm Her2 +. As a result I started anastrozole 5 weeks ago. Okay at first. Joint pain I manage with exercise and a "suck it up and power through it" attitude. However on Monday I got really fatigued and depressed. I wish I could feel better about this drug but with my low receptor % it's hard. My MO agrees but there is not much to do about my values! I will likely end up doing the estrogen sucking drug switch dance. I miss estrogen. We ladies have it for good reason!

annika12

NOT happy with my oncology office Came home from my herceptin infusion to get a phone call that they made a mistake and I received an overdose !!!!! They don't know how much ......slight they said and now I have to have another MUGA before next treatment. My oncologist moved hospital and I can't see HIM til end of January !!!

Moonflwr912

Oh annika! Horrible. I would ask for more fluids possibly? And talk to whichever onc is on call. Maybe getting more fluids would help you get rid of the excess. And perhaps they should do an ekg asap just to make sure you're ok. They didn't mention how much of an overdose? Like double or god forbid x 10? I think you need to pursue some answers. Good luck. Much love. 

annika12

I ended up getting a hold of a doctor at my oncologists new office and spoke to him for some time , really nice of him to call me on a Friday afternoon when I'm not even his patient!! He said to watch and be careful and have the heart test sooner rather then later , like next week. He also said unless the dose was x8-10 there wouldn't be a problem if I'm healthy.....I so want to talk to MY doctor , I am going to try to get a hold of him through my surgeon on Monday !!! Have a happy healthy holiday season ladies , I'm putting this on a shelf for now and enjoying my family

BlueFox

Annika, that sounds so scary, but at least they were upfront about what happened.  I think it would have been even worse if you had an overdose of chemo.  Hopefully no serious harm has been done.

AlaskaAngel,  I don't quite understand your point about chemo.  You are suggesting that the risks and benefits of chemo has not been rigourously evaluated?  Why do you say this?  Originally there was only surgery, then adjuvant chemo was added to the standard treatment (in around 1980s?).  Studies would have been done at that time to establish the risks and benefits of adjuvant chemo (1st generation).  When more effective forms of chemo were introduced (2nd and 3rd generation), trials would have been performed to show that the newer types were more effective than the 1st generation.  When survival is used as endpoint, then this takes account of both lives saved due to treatment and deaths caused by treatment

In relation to radiotherapy, my layperson's understanding is as follows:

 Radiotherapy (in various forms) for the treatment of different types of cancer has been in use for around a century.   Sometimes it was used as palliative treatment for incurable/inoperable cancer.  When it was used as an adjuvant treatment (in addition to surgery), data showed that it was very effective at reducing the incidence of local recurrence but didn't seem to improve survival.  This was because the reduction in cancer deaths was offset by the deaths from late effects of radiotherapy (eg heart damage etc).  However more modern radiotherapy machines and planning make it easier to limit the irradiation of vital organs and thus the risks of radiotherapy are much lower.  More recent data show that modern radiotherapy gives a net improvement in survival.

Chemotherapy and radiotherapy work differently - chemo works on cancer cells throughout the body, whereas radiotherapy only works on cells in the areas that are irradiated.  Radiotherapy saves lives by reducing local recurrences - I've read that around 25% of local recurrences result to distant metastasis and ultimately death, so they are definitely worth preventing.

I'm not sure why radiotherapy is not included in the risk calculators, but perhaps the reason was do with data?  Maybe the type of radiotherapy wasn't recorded in the data analysed?

This would imply that those of us who've had RT should have better odds than predicted by the calculators.

AlaskaAngel

Hi Bluefox,

Given that radiation and chemotherapy each are to be used cautiously for treatment, there are plusses and minuses to both rads and chemo.  So both the plusses and the minuses need to be provided for each patient to consider.

My point is that when patients are only given the rosy data to consider in predictors and no one questions it, or (no offense intended) makes guesses and rationalizes WHY the minuses are left out entirely, then there is good reason to ask why such sophisticated long and diligent and authoritative study of the treatment "just" fails to provide the whole picture for patients to consider.

BlueFox

I agree about the importance of understanding both the pros and cons of treatment.  In the UK, the doctors only recommend a treatment if the pros outweigh the cons, and the NHS don't fund treatments unless there was a clear net benefit.  

If survival is used as the end point in analysis of cancer patient data (and in the calculators derived from such analyses) then this should reflect both deaths avoided and those caused by treatment.  

The NHS Predict calculator shows net benefits of treatments as it uses overall survival (reflecting deaths from all causes).

AlaskaAngel

"If survival is used as the end point in analysis of cancer patient data (and in the calculators derived from such analyses) then this should reflect both deaths avoided and those caused by treatment"

With patients whose net benefit is minimal (and that too is subjective), or for those who have a higher risk tolerance level, "net benefit" may not be as meaningful, and the awareness that a treatment can in fact cause death may be very meaningful.

That is where the unstated "reflection" can be very meaningful in making a decision. If it is never openly said and openly accounted for by a predictor that treatment can cause death, and only included as a "reflection",some patients have no idea that in fact they are taking on that risk.

By emphasizing the "net benefit", without raising the point that treatment can cause death for some patients, the focus overemphasizes the "rosy" viewpoint and understates the unfortunate truth that some patients do die due to treatment. The emphasis with patients who do treatment and then recur and die is never upon "death due to treatment", it is always upon "that treatment didn't work". "Net benefit" is one way of hiding that truth from those who are making choices about treatment.

 

Hindsfeet

For those dx with Her2+ bc Herceptin seems to be a game changer. However, a percentage don't tolerate Herceptin. I took it 5 months at a lower dose and it was toxic to my heart. My oncologist said if I was ever dx with bc again, she would not recommend Herceptin for me. I know of a few women who apparently while on Herceptin had a recurrence???

annika12

We are all individuals and so is cancers  !!! I think you have to find doctors who treat you as an individual not a number !!! Get second opinions ask many question and research. I personally were too overwhelmed to do research but many friends and my hubby were happy to do it for me. I had a friend who passed away 9 wks before I was diagnosed (different cancer) she took a long time to research and went the non chemo rout until it was to late (totally respect her choices) but it made mine easy. I needed to hit it with all I could so I could look my kids in the eyes and say I tried it all, I did all I could !! I went into chemo knowing it would be a fight to keep my body healthy......chemo kills !!! In my case it killed the cancer !!! I never like % cuz what does it matter if it's 95% curable if you are the 5% or the other way around what does it matter if chemo helps 75% if you are the 25% !!!! We all do what we think is right hopefully with the help of great doctors who sees us as individuals not numbers !!!! I am so thankful for all who has been where we are before us who did all the testing all the research ...... 

Ruuthieann

I love your post.  I'm scared. It's been 6 months since my surgery and I haven't been treated yet. Now tomorrow the doctor wants to give me Herceptin only because she said chemo wouldn't help me at this point. The insurance turned it down saying it was experimental. They said I need chemo AND Herceptin. They went ahead and approved it for me anyway but they told me that I should get a second opinion because my doctor is not following the standard care of treatment. I'm afraid that I've metastasized and I have cancer somewhere else because the doctor waited so long.

Girlstrong

Ruuthieann: please get a second opinion and try not to be frightened. Not sure why there was such a gap of time between your surgery and start to meds but your doc must have had a reason. Don't be afraid to ask questions; you can request a PET scan to rule out mets but some docs will only do scans if they are suspicious of mets based on your clinical presentations/symptoms. Herceptin is a targeted therapy for HER2+ and so you will definitely need that; I'm glad you will be getting that soon. Were all here to help so please ask anything; we all need to get through this together. Best wishes....

Ruuthieann

Thanks Girlstrong. I'm concerned if I get Herceptin tomorrow then I can't get chemo. The doctor said it's too late for chemo. I'm thinking about skipping that Herceptin tomorrow since I saw on here some predictor models on here said it would only one additional person out of 100 would live with Herceptin alone.  That's not worth it to me.  I'm going to MD Anderson.  I wish I knew of a good oncologist.  

Girlstrong

Ruuthueann:  MD Anderson  is wonderful and they set the bar in many areas of oncology.  If they are recommendinig that you get Herceptin then they know what they are talking about.  Herceptin side effects are minimal compared to chemotherapy.  You will do well on it.  Good luck!!

BlueFox

Here is the paper I was looking for in relation to prognostic significance of pcR for different cancer types - this relates to earlier posts in this thread.  http://jco.ascopubs.org/content/30/15/1796.full#F2

In relation to the later threads - don't use Predictor models for decision making - decisions should be made after discussions with your onc.  Predictor models never have all your specifics and the data they are based on could become out of date.  They are information only.

rozem

bluefox are we luminalb/herpositive? so that means pcr is not predictive in our case?  ugh that's depressing

Girlstrong

Bluefox:  thanks so much for the article.   Very interesting. 

RoseM: Luminal B referes to ER/PR status.  Since you are triple positive, this research is saying that  "......(pCR) did not correlate with prognosis in luminal B/HER2-positive tumors".  The article later goes on to say that .."Suprisingly, pCR was not prognostic in the luminal B/HER 2-positive subgoup irrespective of trastuzumab treatment,  In this subgoup, pCR rates were low despite concomitant anti-HER2 therapies, but similar outcomes were observed in the adjuvant trastuzumab studies".  Hope this helps.  Keep focusing that you are more that 2 years out from diagnoses and hopefully still doing well, that is a very good thing  

BlueFox

My understanding is that triple positives are assumed to belong to the Luminal B (HER2+ subclass).  The mapping is not 100% accurate, but in the absence of a more sophisticated test (which is rarely given outside of trials), triple positives should assume they are luminal B.

pCR not being prognostic for triple positive is not necessarily bad thing.  People who do get PCR with a cancer that belongs to a group in which pCR is prognostic (ie Triple Negative and HER2 negative (hormone negative)) can feel reassured as their pCR has reduced their risk of recurrence.

But triple positives who didn't get pCR should also be reassured by the fact that it isn't prognostic for them and their recurrence risk is still roughly average for their cancer type, tumour size, number of positive nodes etc etc.

rozem

thanks for the clarification...I guess my disappointment lies in the fact that I was absolutely a surgery candidate as my tumor was only about 2.1 "ish" by imaging and I had no positive nodes (on imaging as well) so going through neo chemo really didn't give me an advantage like it does the other subtypes other than maybe to tell me that the her2 part of my cancer responded - its the ER part that is a mystery in this case.  How can the tumor be completely eradicated and yet the ER cells may survive somewhere else?  ugh ugh and ugh!!!! 

Kayb - I remember you saying that your tumor was low ER/PR - my concern is that I was 95% for both - guess that make me highly luminalb!  this is making me question the ovarian suppression issue, I stopped zoladex due to SE, my period has not returned but if it does I may start them up again

BlueFox

I'm sorry that my burrowing in publications around has led to you being disappointed.  With a small tumour and negative lymph nodes, even an average prognosis is still very good.  And you probably did the right thing by having the chemo.

As far as I know, the result have not been "over-ruled" by any other studies - the St Gallen consensus 2013 is still using this "Residual disease after neoadjuvant chemotherapy appears less important in patients with Luminal A or hormone receptor positive,HER2-positive disease, but pCR seems to be prognostically highly important for non-luminal HER2-positive."http://annonc.oxfordjournals.org/content/24/9/2206.full.pdf+html

Having read a bit more on this, the reason why pCR is not very prognostic for Luminal A and Luminal B (HER2 subtype) seems to be connected to heterogeneity of cancers in the groupings.  

It is known that more aggressive cancers tend to respond better to chemotherapy than indolent cancers and are more likely to achieve pCR.  Getting pCR could mean a) there is a greater chance that it all gone from the body or b) there is a greater chance that you have one of the more aggressive specific types (within the Luminal B(HER2) group).  

If a) and b) tend to more or less cancel out, pCR will be a largely neutral result and perhaps this is what is happening with the Luminal B(HER2) and Luminal A groups, whereas with the other types factor a) is more important than factor b).

rozem

thanks bluefox - your last explanation made a lot of sense

no problem on digging up these studies, I like to be informed and like I said this may push me to re-visit the ovarian suppression issue

dancermom

I wonder if this should give me any comfort or not since I didn't get pCR and I am triple positive.  Interesting that my nodes did get pCR which made me feel good.  Also I was interested that the cancer was grade 3 at biopsy, but what was left at surgery was grade 2.  The difference was the mitotic rate was 3 on biopsy, but 1 on surgery pathology.  Not sure if the cancer changed due to chemo or there was both before.  If there was both before, it was definitely true in my case that chemo works on the fast growing, and not as much on the slower growing cancer.  Hopefully none of the slow growing went anywhere, or if it did, the tamoxifen will take care of it.