ER+/PR-/HER2- Anyone know anything about PR-?

Barbara, my tumor was also ER+ PR- HER2-, so I wondered about the "PR-" too.  First, though, let me clear some things up.  This is going to sound really elementary, for which I apologize; but I want to make sure there aren't any misunderstandings....

"ER" stands for "estrogen receptor", and "PR" for "progesterone receptor".  They are both "hormone receptors" -- the molecular attachment points on (or in) cells to which those hormones bind.

When a tumor is "ER+", it is expressing (synthesizing and displaying) estrogen receptors.  The general assumption is that if a tumor expresses estrogen receptors, it will respond to estrogen by growing faster.  That's the underlying assumption behind the use of "Hormonal Therapy" in BC treatment.  (Note that I'm not mentioning what happens when a cell is PR+, because nobody really knows for sure what role the PR has.)

Tamoxifen is a "selective estrogen receptor modulator," as is Evista (raloxifene).  Think of them as ER blockers.  Both those drugs attach to estrogen receptors and inhibit the binding of estrogen to the receptors.  This supposedly happens on all tissues that express estrogen receptors, including normal breast tissue, uterine tissue, certain cells in bone, ... and, of course, ER+ tumors.  But tamoxifen and Evista don't just bind to the receptors -- sometimes, in certain types of cells, those drugs can mimic estrogen itself and stimulate the receptors (activating the cells).  That's not supposed to happen in breast cancer cells, of course; but it does happen in other cells, like cells in the uterus and bone.  That's what accounts for some of the side effects of tamoxifen and Evista.

Aromatase inhibitors (AI's) are totally different.  They do not bind to estrogen receptors, and they do not stop cells from making estrogen receptors.  (They do not "stop hormone receptors from producing ER.")  Instead, the AI's stop the body from making the hormone estrogen. 

The ovaries normally stop making estrogen when a woman reaches menopause, but a post-menopausal woman continues  to make a very small amount of estrogen in other tissues -- mostly fat cells and the adrenal gland.  In those tissues, an enzyme called "aromatase" is responsible for synthesizing that little bit of estrogen.  The AI drugs act by attaching to aromatase and "inhibiting" it -- they keep it from functioning properly.  Two of the AI's -- Arimidex and Femara -- bind to the aromatase and simply keep it from working.  The third AI -- Aromasin -- attaches to aromatase irreversibly, and causes the enzyme to fall apart and disappear.  The result of "aromatase inhibition" with any of the 3 AI's is a further decrease in the already-small amount of estrogen in a post-menopausal woman's body.

So, can any of this be measured to see if the drugs are working?  Yes and no.  It is not practical to measure the amount of "ER" (estrogen receptor) in the body -- it's a very complicated lab assay, and the amount of ER that would normally be present would depend on which tissue was being tested (and it would require a biopsy).  Also, the amount of ER wouldn't matter anyway, because none of the drugs (tamoxifen, Evista, or the AI's) block tumor growth by stopping the body from making ER.  ER expression on cells is important, though -- it's one of the things that is tested on the original tumor.  The amount of ER expression (the density of ER on/in the tumor cells) is thought to be a predictor of the effectiveness of hormonal therapy:  the greater the ER expression, the better the response to therapy.

It is possible to measure the amount of estrogen in the body; and sometimes our docs will do that, but sometimes they won't.  It isn't relevant if a woman is pre-menopausal or is on tamoxifen, because the amount of estrogen in a pre-menopausal woman is pretty high anyway, and tamoxifen does not act by limiting the amount of estrogen she makes makes.  The AI's, on the other hand, are supposed to suppress estrogen synthesis by blocking the aromatase enzyme.  So, if a woman is on an AI and the drug is working, her estrogen level -- which would already be really low, because she's post-menopausal -- should be even lower.   In fact, it takes a special, high-sensitivity assay to measure estrogen concentrations in post-menopausal women who are on AI's.  The traditional methods can't measure concentrations that low -- everything will be below the threshold of measurement.  As it stands, most oncos don't bother to measure estrogen levels in women on AI's.  I guess the side effects are supposed to tell us they're working.  There is only one dosage used of each of the AI's, and it is not adjusted for weight or body fat content or beginning estrogen concentration.

Now, as for that pesky "PR-"...  It's not clear what role the progesterone receptor ("PR") plays in all of this.  Many oncos think a tumor that is ER+ but PR- will be more aggressive (grow more quickly, be more likely to invade and spread) than one that is ER+ PR+.  Some recurrence risk calculators will report that a woman with an ER+ PR- tumor is at higher risk of recurrence and metastatic cancer than one whose tumor is ER+ PR+.   All else equal, a tumor that is PR- will have a higher Oncotype DX recurrence score than one that is PR+.  That's why I ended up having chemo 2 years ago.

But, the "PR" feature is not taken into account when using ER blocking drugs, like tamoxifen, or estrogen-suppressors, like the AI's.  That might be because, as my first oncologist told me, the PR- feature does not matter -- it's the ER that counts.  Or, it might be because nobody really knows what to do about the PR, and there is no treatment specific to PR- tumors.

I am sorry this is so long.  I spent a lot of time researching "ER+ PR-" tumors, and ended up scratching my head.  And taking my Arimidex faithfully....

otter

Gee Otter, what a great explaination!  I am in the midst of being tested at the moment, although I do know my cancer is ER positive, but don't know anything else such as HER2, PR+ or PR-.  After your post I will be better able to understand where I stand.  I am one of those weird ones with Occult or Cup cancer in which there is no primary source, although probably in the breast as it is ER positive.

thanks Otter for that wonderful information!  I must say I hadn't given much thought to the PR- status - my surgeon just said that the ER+ was the important part but I never really understood about it all. SO thanks again.

Otter, as usual your background, information, and ability to explain things is invaluable.  I'm +/-/- too.  I try not to think about all the articles I've read suggesting PR- is a sign of estrogen resistance in turnor cells.  Makes my stomach hurt.  I sometimes feel like I'm taking Tamox (premenopausal) to prevent a second cancer more than I am to help control the first one.  Then I think of that oncotype score and the fact that that is the recurrance rate ON tamox and my stomach really hurts.  Take my white pill faithfully every morning too.  I also torture myself in the middle of the night with that equivocal but FISH negative H2N.  Get the concept of oncogene addiction.  But wonder sometimes, just because Herceptin only showed statistical benefit in H2N amplified tumors, what if lapatinib would benefit expressing but not amplified tumors?  Then have to tell myself, if it did, GSK sure would have figured it out and been marketing to that huge new audience. 

Check out IIm website. Dr Joe Veltmann checks your DNA to see what caused your cancer and recommends Nuttrional supplements to help prevent reoccurance and get your Immune sytem in tune

Ruth,

I'm glad that you and others have had positive experiences with the AIs.  I, and many others, are not so fortunate.  The joint pains are bad enough by themselves, but add the near-crippling fatigue and it's really hard to take (this is my second AI and I've had similar experiences with both).  I have been trying to exercise but I can only get in 3-4 hours of very very mild activity (light household chores, running errands) before I hit the wall.  And this is from a person who used to be very physically active, even through chemo. 

Yes, anyone who needs AIs should try them with an open mind.  However, there are those of us who experience terrible side effects.  We are not lazy wimps who refuse to exercise.  We are in trouble.

E

Nope - I progressed on Tamoxifen.

Sure does!  But I'm NED now and hoping that Arimidex keeps me that way for a long long time.

:-)

enjoyful, I am very happy to hear that you are NED. I don't know how long you've been on it,  but for some  people, the SE of arimidex level off once their body adjusts, and I hope that will be the case for you. All my best. Ruth

It's good that you are keeping moving, even though it isn't much fun. I do think that can help, some anyway.

The fatigue takes time to resolve. When you think of everything that we've been through both physically & emotionally, it would be strange if a person weren't exhausted!!! Things I've read say that for however long you are in 'active' treatment; it should take that long again to feel 'normal'; I'd say to double that amount of time. For me it took about a year to think, "Wow, I actually feel good again." I do think that getting some exercise does help (even though that's about the last thing you want to do).