Topic: How Long on AI's, and what are the cells doing?

Ah... the question of the hour, Flashdif. I've been thinking and studying since you posted in September! Totally voluntarily of course, admixed with personal reasons.

I'd like to refer you to one clinician/researcher reference, Paul E. Goss, M.D.,Ph.D., medical oncologist at Mass General Hospital on estrogen suppression in the ER+ state. I'll paraphrase my understanding of his remarks and also give you a reference/link where, should you choose, you can listen to his words:

a. Foremost, he emphasis is on the mind-boggling necessity of women with ER+/PR+ disease to understand the long chronicity of relapse in the hormone positive state. We've all heard stories of women living 20+years in the now older literature ( I read one report at 40 years), and having a late advanced recurrence. He and other oncologists see these patients. So for that reason, clinical trials with AI's long-term are being undertaken with the hope of success of abeyance of progression, even with recognition of long term chronic side effects. Dr. Goss is a letrozole man having studied it in the MA-17 clinical trial (where Tamoxifen was used first, then letrozole vs placebo with unblinding and allowed switch from TAM to letrozole, then letrozole again, each in 5 year succession).

b. What backs this up? The chronicity of low percent recurrence of ER+ cancer (but adding up all the recurrence, contributing to the 40,500 annual U.S. deaths/year). Two clinical studies with results do so:
The Oxford Study of England, largely reported on by Richard Peters, M.D., and the MA-17 study of Canada as reported by Dr. Goss and others. Both are giving results out to 15 years. Both suggest the annual hazard rate for recurrence in ER+ patients after initial 5 years Tamoxifen is: 2% annually for node negative, 4% annually for node positive.

c. By taking letrozole which the MA-17 uniquely used in the second five years vs placebo (sorry, can't comment on interchangeability of AI's), this resulted in an " absolute median disease free survival advantage of 4.5 % in 4 years "( direct quote). His conclusion is that doing such, sticking with Letrozole past 5 years to 9, 10 years "basically erases the chance of disease (...progression)" .. using an AI if you give it long enough".

So, how long on AI's, Dr. Goss would suggest a long time. Here is the reference to this information:

http://www.breastcancerupdate.com/2005/covers/default.asp Go to audiofile, click on Dr. Goss, and go to number 11 and 12 earphones and you'll here him speak.

Two points I could not resolve: how a 4 year 4.5% DFS advantage with Letrozole meshes with a 4% annual recurrence for + nodes, and "erases risk". I'm thinking on this point still.

Second: Can this information be extrapolated to other AI's (probably not exactly, but somewhat) and what about switching between AI's (non steroidal to steroidal) to keep the potential bc cells confused by changing hormonal action. This is being studied too.

As to your questions "What are the cells doing"? Well, that's a topic for another day...

All the best ladies,
Tender

I'm not the smart one here.   Tender is one of our geniuses. 

I can't put ANYTHING I'm saying into medicao lingo.  However, with recent studies I thought it was believed that ER/PR+ women were supposedly getting better with results than with chemo. 

My original onc had me do AC/Taxol dose dense, them I had mast, then rads and THEN I did six months of Xeloda FULL STRENGTH.  He left Duke and my "now" onc disagreed with his treatment as far as the Xeloda was concerned.  I suggested to her that perhaps he was thinking that since I still had 5/7 nodes + with extranodial extension AFTER chemo (my tumor shrunk about 1/2), that he wanted to "cover his basis" and try to get those sneaky little stay cells.  She said that Arimidex would have done the job.

All this stuff gets so confusing.  Thus, do we rely on the fact that chemo did SOMETHING (hopefully), or hope that the AIs are mopping up and cleaning out and killing those buggers (cells)?

Shirley

Okay, I'm a bit confused (which isn't too hard to do to me these days).

Am I understanding this correctly, that for us node positive women, the risk of recurrence is cumulative at 4% per year. So in the first year post dx, it's 4%, the next year it's 8%, the year after that it's 12%.

Is this correct, or am I misinterpreting here?  If I am getting this right, it's pretty scary.  It means that at the very best I can hope for 25 more years???

My onc. said that unlike other cancers, the threat of recurrence never goes away, but he did say that it goes down slowly over time, with the majority of recurrences happening in the first 2 years.

Can someone please clarify this for me.  It would really help me with regards to how long to try and tolerate the se's from Aromasin.

Flashdif--I have often wondered about the non-ER+ cells as well, but have never been able to find out any research or info on that. 

Thanks,

Eileen 

Tender

Are you a chemist? Medical professional? I am in awe of your knowledge and your research!! You know so much more than just the sound bites that make the news. I truly appreciate you sharing. I admit that I have to read the information several times to begin to understand it. I am NOT a numbers person-that is part of the problem.

Do you have much research about node negative women and long term AI usage? I am a late stage 1 and have a  generally good longterm prognosis in terms of survival and living disease free. I was diagnosed premenopausally, though (age 43) with one of my tumors high grade, ER/PR pos, Her2neu neg.  That is one of the reasons I asked about how women 10, 15, 20 years out present when they have a re-occurrence. As I understood my risk when first diagnosed, I have a decent chance of never having BC again. I am inclined not to continue on Aromasin past 5 years due to side effects mentioned above and lack of knowledge about the longterm effects of AI's.  I have plenty of time yet to decide, 18 months.

Well, Tender, who knows who's right?  I know at Duke they meet each Monday (I think) to discuss patients.  So, I'm wondering who was in favor of my doing Xeloda OR not! 

No, I'm not tough.  Just the opposite.    But I AM nuts! 

I believe Nosurrender, Gina, had almost the same treatment with her second bc.  Her first bc was ER-.  Her second breast was ER+ with 4 nodes postive with extranodial extension.  Her onc gave her Avastin and Cytoxin (I think...I have brainitis) and also Xeloda.  I say she's the tough one.  She's gone through this crap twice.

I'll have to reread your post later or copy it and study it later.  My elevator only goes up to, maybe, the third floor.   I hope the elevator doesn't stop all together.

I love these little Emotions or Gremlins.  Did you notice? 

I must go do my hair.  I think my "Gypsy" children from the dark side of the world may just show their faces this evening.  They've been out of town for 10 days visiting brothers, sisters, sisters-in-law, brothers-in-law, nephews, niece and friends.  But who's counting how many days those kids have been gone.  They'll be leaving back for Africa Tuesday. 

Shirley

DR LOVE: Overall, what is the biggest misconception of oncologists in practice with regard to endocrine therapy?

DR GOSS: I’m heavily biased here, but I believe the greatest disservice to women with breast cancer — other than possibly overtreating with chemotherapy in certain circumstances — is the lack of understanding of the chronicity of relapse in hormone-dependent breast cancer, the benefits that can be obtained by aromatase inhibition and the easily manageable level of toxicity that’s associated with that therapy.

DR LOVE: Do you believe that aromatase inhibitors are underutilized?

DR GOSS: Very much so, specifically with regard to the use of extended adjuvant endocrine therapy. In the MA17 trial, postunblinding, we offered letrozole to 2,500 patients who had been on the placebo arm, and we found a continuing benefit to introducing letrozole in patients who had finished tamoxifen one to 10 years prior (Goss 2005a).

DR LOVE: What about investigating even beyond that? Is that in the realm of chemoprevention?

DR GOSS: You put your finger right on the misunderstanding of this disease. Most oncologists imagine that with the passage of time, the proportion of relapses, including metastatic relapses, declines. However, we do not see that in the Oxford overview (EBCTCG 2005) or the MA17 data (Goss 2005b).

Two thirds of all recurrences in node-positive, hormone-dependent breast cancer, no matter how far out you go, are metastases. Among the patients with node-negative disease, if you add up local-regional, contralateral, new primary and ipsilateral recurrences, they come to 60 percent, but 40 percent of all recurrences and the most frequent single site of recurrence are metastases, and they’re fatal.

The benefit that we’ve shown for letrozole is an absolute median disease-free survival advantage of 4.5 percent in four years, and all the data suggest that this will continue for 15 or 20 years. You can erase the chances of recurrence of breast cancer with aromatase inhibition if you keep administering it for long enough.

Tender........am I understanding this correctly, that the 2-4% yearly risk starts after 5 years on Tomoxifen or do you start counting your risk the 1st year you are on Tomoxifen?

Terry 

Rumoret, my understanding is the risk for recurrence is highest the first 5 years and then somewhere between 5 and 10 years, reduces to 2% (for node negative ER+ women) and 4% (for node positive ER+ women). So this would be after 5 years of Tamoxifen as illustrated in the above referenced Oxford Overview and MA-17 (Canadian) study. For the MA-17 study, Letrozole was given to half for the second 5 year period and the other half of the ladies received a placebo. Due to a statistical improvement in DFS from Letrozole, the results were unblinded early and the placebo women offered Letrozole. For those women who accepted the new Letrozole, they continued to have a noticeable DFS suggesting that Letrozole is effective when resumed after being off of a hormonal for ER+ disease.

This last point is important, as many women stop or stopped at 5 years with their hormonal. I've seen a number of ER+ threads asking: is it too late to start on a hormonal. The clear answer then, is no. This was a great value of the trial. But the years of study only are up to 10+ (don't know exact year the MA-17 is just now). But for women 20 years out with ER+ disease, no one knows.

One question that I ask: is this information interchangeable with all AI's? The ATAC (Arimidex, Tamoxifen, Alone and in Combination) data, and the IES study (Intergroup Exemastane Study) on Aromasin is similarly strong for early DFS, but curiously only Letrozole has seen statistics demonstrating efficacy in preventing late disease recurrence. I'm pondering this one. Is it the degree of estrogen reduction (highest with Letrozole), the chemical structure of Letrozole having some as yet unknown effect on nuclear gene translation) or something else?

So WhiteRockGirl, the number for later years node negative recurrence is 2% per year ( after 5 to 10 years on hormonals, depends on who you talk to whether it's 5 years or 10), and you would run the numbers the same way as illustrated above. Yes, I was in the health profession field, and I passionately read, as I believe there is much strength in sharing and helping women and men to understand, even outside of their personal visits. Yet I am no expert in bc, but a sister joined by disease and with joined arms.

Shirley, I am still of the mind you are strong. And I can see this too in your daughter's beautiful face, just like Momma.

Tender

Yes, if you are an appropriate candidate for use of an AI, and willing to use them, as opposed to unable/unwilling for other valid reasons (like bone loss concerns,etc) all studies (ATAC for arimidex, IES for aromasin, and MA-17 for letrozole) point to greater early DFS (disease free survival); Letrozole also reduces later disease recurrence. So, jmo, I would switch from Tamoxifen to an AI, and now that I am aware of the later disease recurrence reduction, Letrozole does sound appropriate.

In several years, additional MA-17 Letrozole statistics will be available, as will the BIG I-98 all of which should provide additional evidence base medical decision making.

These hormonals work against ER+ breast cancer. As long as we take the pill.

All the best to everyone,
Tender

Thanks Tender.........I appreciate you opinion........I'm leaning that direction, but will have to talk this all over with my oncologist and see what his educated opinions are.

Love,

Terry 

Member, I believe the MA-17 trial was for 5 years of Femara after 5 years of Tamoxifen.  The results did show those taking Femara after Tamoxifen had less recurrences, especially those with positive nodes.  You might find the results interesting to read, especially since you had a positive node.  I removed my ovaries and am on Femara and I still exercise on a regular basis.   

I do have musculoskeletal pain but it is mainly in my upper arms, shoulders and neck.  It is hard to tell if the pain I feel in those areas is from Femara or from having tight pectoral muscles from my bi-lateral, reconstruction and rads.  I am currently in physical therapy and have been told that my pain is probably from extremely tight pecs so it may not be from Femara.  I believe the loss of estrogen increases ones sensitivity to pain.  If you already have arthritis or a weakened joint then the pain can be worse.  I took Arimidex first and did not have as much pain but had some stomach issues.  I also took Tamoxifen for 3 months before my ovaries were removed.  I didn't notice that much difference from Tamoxifen and Arimidex; however, the pain from AI's may be cumulative as the estrogen in your body lowers. 

I was dx stage iv in May 06, started on Tamox. for about 4 months then switched to Arimidex.  I have some joint discomfort, especially in my hands but other than that, no SE's that I really notice.  Bone scans and densities have come back good.  My ca 27.29 is usually below 20, most recently 11.  So, I feel like I can continue the Arimidex forever.  I also have been having monthly treatments of Zomeda which just recently were changed to every other month, part of the reason for that is that my creatnine level was 1.3, the high end of my baseline.  Apparently the zomeda is rough on my kidneys.  I ski and took a couple of good tumbles this year with no problems though, so the zomeda must be doing something right.  So definitely add me to the group that wants to keep taking Arimidex!!