Understanding Tamoxifen to prevent mets and recurrence

Colleoni et al. recently reported results of one study in both ER+ and ER- patients with a median follow-up of 24-years from diagnosis of operable breast cancer. Results from five prospective and randomized IBCSG studies, including 4,105 patients randomly assigned from 1978 through 1985 were reported.

They found that ER+ patients (like everyone else) were at greatest risk in the first 5 years, and that the hazard decreases thereafter. See Table 2 in the PDF version below, showing hazard of recurrence by 5-year intervals according to ER status (ER+ versus ER-) among various subgroups defined by number of positive axillary nodes, tumor size, grade, menopausal status or treatments (observation, chemotherapy alone, hormonal therapy +/- chemotherapy).

"Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V"

Colleoni (2016): http://jco.ascopubs.org/content/34/9/927.abstract

A complete pdf copy of the paper is now available for free under the PDF tab.

From the full-text:

"For the entire group, the annualized hazard of breast cancer recurrence was greatest for the first 5 years (10.4%), with a peak interval between years 1 and 2 after surgery (15.2%; Fig 2A). The hazard decreased consistently during years 5 to 10 (4.5%) and then remained stable. During years 10 to 15, 15 to 20, and 20 to 25, the hazard of recurrence was 2.2%, 1.5%, and 0.7%, respectively (Table 2)."

Please note the following:

-- For the entire group, the annualized hazard of recurrence was highest during the first 5 years.

-- For the entire group, the annualized hazard of recurrence showed a peak between years 1 and 2 after surgery.

--The hazard fell off in years 5 to 10, and then persisted at a low level over time, particularly for ER+ disease.

-- Comparing ER+ versus ER-, they observed a statistically significantly lower hazard of breast cancer recurrence for patients with ER+ disease versus those with ER- disease during the first 5 years (9.9% v 11.5%; P = .01). However, the hazards of ER+ and ER- disease crossed between years 2 and 3, and beyond 5 years, the hazard of recurrence was higher for patients with ER+ disease compared with that of those with ER- disease. (See curves in Figures 2 and 3)

NOTE: This is NOT saying that that the annualized hazard of ER+ patients increases after 5-years, but only that their annualized hazard remained higher than that faced by ER- in later time periods.

Long-term follow-up studies will always have inherent limitations. Unfortunately and fortunately, by the time the study is concluded and results are obtained many years after enrollment, the standards of care will have evolved and improved.

In this particular case, there have been significant changes in systemic treatments (including the use of 5-years of endocrine therapy versus one year or ovarian suppression alone) and in radiation therapy, so that patients diagnosed more recently may fare better than these numbers indicate. In addition, the study population was relatively diverse, so those with more favorable prognostic features may also tend to fare better than than the group as a whole. Both of these would apply to your situation. Thus, while the measured hazard rates may differ today, the general trends about risks over time are informative.

Here is a recent meeting abstract and news feature from a large study out to 14 years:

"Predictors of recurrence during years 5-14 in 46,138 women with ER+ breast cancer allocated 5 years only of endocrine therapy (ET)"

Pan Abstract (2016): http://meetinglibrary.asco.org/content/166053-176

Note that the "cumulative risk" in column 4 are the combined annual risks over multiple years, and do not mean risk is increasing over tiime.

ASCO Post re Pan (2016): http://www.ascopost.com/issues/july-10-2016/ebctcg-analysis-identifies-recurrence-risk-by-tumor-subgroup-in-estrogen-receptor-positive-breast-cancer/

Such meeting abstracts may report interim results, may be preliminary in nature, and/or contain errors in data / analysis, and it may not be appropriate to rely on such findings for treatment decisions.

More modern studies that reflect individual diagnosis and treatments as closely as possible may be better guides for patients, but unfortunately, they often do not have such long-term follow-up. Advice from your MO about your estimated recurrence risks and the risk/benefit of any proposed treatment is most important for your current treatment decisions.

BarredOwl

Hi lcantri:

I included the initial information and link to Beesie's post as background for other readers re the nature of the risk and purpose of systemic treatment.

Re: "Assuming there is no node involvement, why do they use Tamoxifen for 5 years?" As noted above, because there is a possibility of current micrometastatic disease, and Tamoxifen has been shown to reduce the incidence of incurable metastatic disease.

Re: "I have read that hormone receptor positive bc tends to recur later than 5 years." I provided studies that show that you are correct that hormone receptor-positive disease can recur after 5-years. However, the annual recurrence risk is greatest in the first five years (peaking in the first few years), and after five years, the annual rate declines over time.

Re: "So if it is going to rear its ugly head aren't we just delaying the inevitable?" It is true that despite receiving tamoxifen treatment, some patients still suffer distant metastasis, but not all. Treatment is effective in many patients and distant recurrence is not "inevitable". That said, delaying the onset of metastatic disease (in those who may eventually suffer distant recurrence) has benefit in terms of quality of life and survival time.

Re: "Why not let it run its course and deal with it sooner rather than later?" I thought you might be asking why not skip endocrine therapy, if it can still recur after 5-years, particularly in view of your reference to "delaying the inevitable". Unfortunately, letting "it run its course" could lead to incurable metastatic disease, particularly for those at greatest risk, which is why it should be dealt with sooner rather than later. Maybe you answered your own question: To "deal with it sooner rather than later" implies the opposite of letting it run its course, and current practice is to deal with it by treatment in the first five years.

By the way, some patients receive 10-years of endocrine therapy, if their continuing late recurrence risk is sufficiently high and their personal risk/benefit profile warrants it. Of course, the lower risk, the lower the risk reduction benefit of treatment. For many, the lower recurrence risk in later years (and commensurately lower risk reduction benefit of therapy) may not warrant continued therapy.

Sorry if I didn't answer your question clearly or am still misunderstanding it.

BarredOwl

Hi Icantri:

Re: 1 What if I don't have any mets, then I don't want to take meds.

Indeed, but the problem is that today, we have no reliable method to prove the absence of current micrometastatic disease in a patient. Thus, systemic treatment decisions depend upon population-based risk assessments and what they say about the likelihood of suffering distant metastasis, based on certain features of the disease.

Factors considered in systemic treatment decisions include histology (e.g., ductal, lobular); actual tumor size; lymph node status; hormone receptor status (estrogen receptor ("ER") and progesterone receptor ("PR")); and HER2 status. The results of gene expression profiling tests on the tumor (e.g., Oncotype DX in certain patients with hormone receptor-positive, HER2-negative disease) may be used if indicated. In addition, grade and lymphovascular invasion, as well as age and health history (e.g., co-morbidities), can be considerations.

From your posts, it looks like you have not had surgery yet? The information from biopsies, together with the results of the surgical pathology and sentinel node biopsy, plus any additional test results, such as OncotypeDX (if appropriate), will provide more information needed to inform decision-making about endocrine therapy (for hormone receptor-positive disease), chemotherapy, and/or HER2-targeted therapy (for those with HER2-positive disease).

Your estimated recurrence risk, the potential risk reduction benefit of each treatment, and the risk of severe adverse events are part of the personalized risk / benefit analysis used to decide these questions.

Re: 2 If I do have mets I would rather have chemo now instead of waiting for them to take hold and be harder to stop.

Again, unless positively diagnosed with metastatic disease at the outset, there is no way to be sure about this (see above). Chemotherapy appears to be more effective on certain types of disease than others. Also, the potential risk reduction benefit of chemotherapy is bigger in patients at greater risk of recurrence. In some patients deemed to be at much lower risk of distant recurrence, the potential risk reduction benefit of chemotherapy may not outweigh the potential risk of serious adverse events. [Edit: In the appropriate case, endocrine therapy alone is the recommended treatment.]

Re: I think maybe I wasn't seeing Tamoxifen as a treatment so much as a suppressor, if that makes sense.

That is an interesting observation and it may have features of both, based on its ability to reduce the incidence of metastatic disease. Due to its ability to inhibit the growth-stimulating effects of hormones on tumor cells by blocking hormone action on receptors in breast cells, Tamoxifen has traditionally been viewed as a "cytostatic" agent (versus as a tumor cell-killling "cytotoxic" agent). However, other phenomena might be in play in those receiving endocrine therapy, such as immune surveillance and/or making cells susceptible to apoptosis (killing themselves).

BarredOwl

BarredOwl - ditto - your posts are always so helpful. Thank you.

Misty,

There is no guarantee that cancer cells have not entered your bloodstream. After all, cancer needs a blood supply to grow and become invasive. But, the fact that your lump was relatively small and cancer did not make a home in your lymph nodes is a very good thing. You have a very good chance of living cancer-free!

Elaine,

That's what I was basically asking, what you answered. Is there a chance (perhaps even a good chance) that no cells escaped the original tumor and that there are no other cancer cells elsewhere in my body from the original breast cancer. I guess I wasn't sure if that could happen where surgery really does get it all and nothing traveled anywhere.

Re: "But the thing that confuses me I guess is that if no cancer got outside my breast then that 20-30% doesn't include metastasis but more so would include a new cancer happening in the other breast."

I don't think that is a proper way to look at it. A measurement of X in a clinical trial is a measurement of X. It is not a measurement of Y. It does not include Y.

They measured a specific outcome or "event": distant metastasis. A statistical measure of a specific thing happening (i.e., 10-year distant recurrence events) does not morph into a measurement of something completely different (e.g., local recurrence), just because a patient (who is not part of the study) does not experience the event.

There is no way to know whether or not some cells have left the breast in an individual patient. To get an idea of how often that occurs, leading to overt metastatic disease, a group of patients was studied. They measured or counted occurrences or "events" of distant metastasis. The 10-year risks of distant recurrence presented in the node-negative report are based on observation of a group of node-negative patients, and what happened to them after 10-years distant recurrence-wise.

The test is "prognostic", and these data indicate that among those with a Recurrence Score of 24 who receive tamoxifen alone, after 10 years, about ~15% would suffer a distant recurrence, while ~ 85 % would not (see your report and Figure 4 below).

That is a statistical measure or percentage measured in a group. It gives you an idea of the odds of a similarly situated person (receiving tamoxifen), with the same recurrence score, suffering distant metastatic disease in the next ten years, based on what was observed in the group.

Unfortunately, these statistical risk measurements cannot predict individual outcome: In an individual patient, something either occurs or it does not. Whether a specific person (with RS of 24 and taking tamoxifen) will fall in the 15% or 85% cannot be known.

This is the original study report that is the source of the information in graph 1 of your node-negative report:

Paik (2004): "A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer"

Main page with Tools (pdf, Supplementary Materials): http://www.nejm.org/doi/full/10.1056/NEJMoa041588#t=article

PDF copy: http://www.nejm.org/doi/pdf/10.1056/NEJMoa041588

This is a scientific explanation of what they counted:

"The first prespecified primary objective was to determine whether the proportion of patients who were free of a distant recurrence for more than 10 years after surgery was significantly greater in the low-risk group than in the high-risk group. The second prespecified primary objective was to determine whether there was a statistically significant relation between the recurrence score and the risk of distant recurrence — one that went beyond the relation between recurrence and the standard measures of the patient's age and the size of the tumor. Contralateral disease, other second primary cancers, and death before distant recurrence were considered censoring events. Recurrence in the ipsilateral breast, local recurrence, and regional recurrence were not considered events or censoring events."

Please ask your MO: (a) if that means that the 15% measured does NOT include contralateral disease, other second primaries, same in-breast recurrence and regional recurrence; and (b) that those other types of events would present additional risks (of loco-regional recurrence or of new disease (new primary, contralateral)) over and above the 15% distant events.

There may be errors in my understanding or explanation. Patients need to understand the size and type of risks they may be incurring to make an informed decision, and should not hesitate to seek clarification from their MO to ensure accurate understanding of the advice they have received.

I do not know what is the current recommendation for follow-up imaging on a person with nipple-sparing and implant, or what kind of imaging would be used, if indicated. The American Cancer Society suggests:

http://www.cancer.org/treatment/understandingyourdiagnosis/examsandtestdescriptions/mammogramsandotherbreastimagingprocedures/mammograms-and-other-breast-imaging-procedures-mamm-after-breast-cancer

"Women who have had a subcutaneous mastectomy, also called skin-sparing mastectomy, still need follow-up mammograms. In this surgery, the woman keeps her nipple and the tissue just under the skin. Often, an implant is put under the skin. This surgery leaves behind enough breast tissue to require yearly screening mammograms in these women.

Any woman who's not sure what type of mastectomy she has had or whether she needs to get mammograms should ask her doctor."

There may be exceptions, and this may or may not reflect current clinical practice. Therefore, please seek case-specific expert advice from your oncologist and plastic surgeon regarding the recommended modalities and frequency.

BarredOwl

Does anyone know what the average woman's risk is of developing breast cancer period. Like not someone who has been previously diagnosed.

This page from NCI discusses average lifetime risk and risk by decade:

https://www.cancer.gov/types/breast/risk-fact-sheet

BarredOwl

Hi dollyfappa:

There are some differences in the way ILC versus IDC is approached in the clinic. For example, there is some indication from clinical trials that aromatase inhibitors may have some advantage over tamoxifen in ILC (see, introductory materials below). In view of this, and to get more responses from those with ILC who have faced similar decisions, you may wish to start a new topic in the ILC Forum found here:

LINK to ILC Forum: https://community.breastcancer.org/forum/71

At the top of the page, you'll see this:

Click the pink button (Start a new Topic) to enter a title and then the text of your post. You can copy and paste your post from here.

You may also be interested in recent posts from this large thread regarding Anastrozole (Arimidex):

"Topic: For Arimidex (Anastrozole) users, new, past, and ongoing"

https://community.breastcancer.org/forum/78/topics/790338?page=461#post_4901499

Perhaps you can revert to your MO for some additional discussion of the risks of bone loss presented by an aromatase inhibitor, the risk / benefit profile of actonel, and whether monitoring bone density prospectively is a reasonable option to bisphosphonate therapy with Actonel in your particular circumstances. Optionally or in addition, you may wish to seek a second opinion on this question from another medical oncologist. For a possible second opinion, if feasible (confirm in-network), an NCI-designated cancer center may be a good option:

NCI-designated Cancer Centers: https://www.cancer.gov/research/nci-role/cancer-centers/find

If on the other hand you will be taking the tamoxifen, did you discuss your medical history of uterine polyps with your medical oncologist? In case it is potentially relevant to tamoxifen treatment and monitoring, he should be made aware of your gynecologic history. (He should also be informed of any medical history of blood clot.)

Best,

BarredOwl

The following are provided as background information only. If these influence your thinking in any way, be sure to discuss them with your team to ensure accurate understanding and applicability to your case.

Barrosso-Sousa (2016), "Differences between invasive lobular and invasive ductal carcinoma of the breast: results and therapeutic implications:

"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4952020/pdf/10.1177_1758834016644156.pdf

Sledge (2016), "Collective Wisdom: Lobular Carcinoma of the Breast"

http://meetinglibrary.asco.org/sites/meetinglibrary.asco.org/files/edbook/176/pdf/EDBK_100002.pdf

ASCO Post (2015): "Benefit of Adjuvant Letrozole vs Tamoxifen Is Greater in Lobular Than in Ductal Breast Cancer"

http://www.ascopost.com/News/31718

Metzger Filho (2015), "Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial"

http://ascopubs.org/doi/full/10.1200/JCO.2015.60.8133

(pdf version available under PDF tab)

Knaer (2015), Abstract, "Survival advantage of anastrozol compared to tamoxifen for lobular breast cancer in the ABCSG-8 study"

http://cancerres.aacrjournals.org/content/75/9_Supplement/S2-06

Findings may be preliminary.

Hadji (2016), "Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel"

https://academic.oup.com/annonc/article/27/3/379/2196531/Adjuvant-bisphosphonates-in-early-breast-cancer

(pdf version available - button above abstract)

Review re Bisphosphonates by a European panel (may differ in some ways from our local practice)

Hi Fe_Princess:

No, I would not say that! Recurrence risk information is statistical in nature and does not predict individual outcomes. This type of information only speaks to the odds of recurrence, not to which person will or will not suffer a recurrence. Those who decline or discontinue treatment early may have higher odds of recurrence than they would if they were able to complete five years of therapy, but some proportion of them will still never suffer a recurrence. Even among those who do complete five years of treatment, recurrence is still possible (because treatment is not always successful).

Re the recurrence risk information and Recurrence Score you received:

Here you noted: "After my mx, I saw my MO who told me that my recurrence risk was 36% but then my surgeon told me that since my oncotype dx was 18, I did not need it."

In another post you noted: "I saw my oncologist and she said I was high risk 36% for recurrence and wanted me to start chemo right away. I asked for an oncotype dx and it came back 16 so I did not get any chemo. . . I was not menopausal before my oophorectomy either."

I am not sure what type of risk estimate the "36%" was (e.g., risk without any systemic treatment? distant recurrence risk only? 10-year?). However, it sounds like it was provided before the Oncotype test was done, and is not based on the information in the Oncotype report. Also, you received some Tamoxifen before discontinuing it.

===> If you have not already done so, please obtain a copy of your Oncotype report for your review and records and to verify:

(1) the actual Recurrence Score; and

(2) the associated 10-year risk of distant recurrence with Tamoxifen Alone. It is printed next to the first graph (at left) in the node-negative (N0) reports.

Some information and advice you may wish to seek:

===> If of interest, you may wish to ask a Medical Oncologist to provide you with a REVISED estimate of your 10-year distant recurrence risk with no endocrine therapy, based on the information in your Oncotype report (which is based on tumor biology). The report itself does NOT include recurrence risk with no Tamoxifen (because the focus is whether or not to add chemo to endocrine therapy). However, in some cases, MO's here have provided an estimate of 10-year distant recurrence risk with no endocrine therapy (e.g., by extrapolating from the information in the report and the known risk reduction benefit of Tam (about 45%)).

I never received such advice myself and as a layperson with no medical training, I am not qualified to advise you. But if you received a node-negative (N0) Oncotype report and a Recurrence Score of 16 or 18, then my layperson impression is that a revised estimate (10-year distant recurrence risk with no Tam) should be lower than 36% (It depends on the risk with Tam Alone printed in your report). If so, receiving a revised estimate from an MO might ease your mind.

===> You may also ask the MO whether you took Tamoxifen long enough to reduce recurrence risk somewhat from the REVISED risk estimate.

By the way, if you received bilateral oophorectomy, you are by definition "post-menopausal" for the purpose of endocrine therapy per NCCN guidelines, and would have the formal option of receiving an Aromatase Inhibitor ("AI"). Tamoxifen and AIs have different side effect profiles, and some patients may tolerate one better than the other, although not always.

===> If an AI would be of potential interest to you, at the same time you could also seek expert advice re whether or not initiating AI therapy at this time may be worth considering in your specific case, despite a gap in treatment. You should provide the MO with a copy the Oncotype report in connection with any such inquiry.

BarredOwl

I am very sorry that you are now dealing with skin cancer too and send my wishes for your treatment.

Inquiring about a new MO seems like a good idea. Her statement: "I will see you in two years with [recurrent breast] cancer again" is not accurate, because it cannot be known (i.e., she cannot predict individual outcomes with certainty, and if the risk was ~36%, the odds would still be in your favor).

A couple of members here with a node-negative (N0) report and RS = 18 indicated that the 10-year distant recurrence risk (with 5 years Tamoxifen) given in their report was 11% (WITH TAM ALONE). That seems about right, if you eyeball Figure 4 in my post of November 20 above. A revised 10-year distant recurrence risk estimate taking into account the Oncotype risk information to the extent appropriate in your specific case** might be be a chill pill of sorts, and would be important to have in connection with any further discussion of the risk/benefit of possibly resuming treatment or not.

BarredOwl

** Which POSSIBLY might be somewhere around 20%??? to 22%??? based on the test output alone, but please be certain to seek expert advice re your estimated recurrence risk from an MO familiar with all the relevant clinical (e.g., age), pathologic, and available test information in your specific case.

Thank you for all of this wonderful info! I wish my first MO would've just given me this link. LOL. Very very helpful in understanding what everything really means. Even 6 months after RADs I'm still learning! Thanks again!