Does it really matter what "treatment" we take?

Miley:

You could go the route of many. Try the anti-hormone and if too many SEs, you quit. But it not, another level/layer of protection. (I'm having few SEs from Tamoxifen...not on AIs yet.)

Busombuddy, letrozole is way out there for arthralgia, my top complaint. Also it shows cognition down the line. Thirdly it doesn't show eye problems but then they might not have connected the dots. I see Tam is worse than Let in many cases. 18.9% quit, good to know. So it would be 61% of 18.9%. So 11.5% of all quitters (not just letrozole) at risk for DFS? It's hard to read the chart. Thanks. Correct me if I'm wrong. Very tired.

Hapb - excuse my serious chemo brain. Are you saying that Stage1b has almost as good prognosis as stage 1a or that after stage 1a it's a crapshoot and it is the same as later stages

I don't know bosom. I found the 61% and the 18.9%, they mentioned 29 other studies (smaller?). I think maybe the 35% to 56% might be referencing something else? But you saw that Novartis funded the study so it can't be trusted anyways. There is an article posted yesterday about pharmaceuticals finaancing studies did you see it? Interesting the drop out median was at 19 months and they were only requied to take 80% of their pills and the lost 273 results?

I went 28 months. Tell me how this applies to you and I'll give you my opinion.

From the study:

There were 51,218 drug-pack records in the database; 273 (0.5%) had missing compliance information (Table 1). Figure 3 summarizes the distribution of DFS events according to the compliance score dichotomized at 90%. Results from the Cox regression model show that among women who completed study therapy, there was a statistically significant 61% increase in the risk of a future DFS event for a compliance score of < 90% (HR, 1.61; CI, 1.08 to 2.38; P = .02).

mom is 58, we are waiting for thew answer of post operational biopsy , she had surgery yesterday , radical mastectomy and one lymph node was metastatic, doctor told me that treatment depends on biopsy answer perhaps she is going to determine oncotype. thank you for your answer . I really appreciate it.

Marijen,

I was just recently diagnosed and I'm still recovering from a bilateral. I haven't started taking hormones yet and I'm seriously considering opting out. Everyone is different and it seems right for me given my stage and the characteristics of my tumor. I'll have to look at the pharmaceutical article you mentioned.

Pupmom, I'm curious. How long have you been using TAM

As I see it, to use Pupmom's analogy of Russian roulette, taking tamoxifen is also its own kind of roulette. It's not like taking tamox doesn't come with its own risks. Side effects, some of which include the possibility of other cancers and blood clots. So it is not an accurate picture to believe that taking a hormonal will save us from the blight of cancer. It might, it might not. It might even leave us worse off! Depending on how you view the world I see it more as a Mexican stand-off. Cancer is pointing a gun at me, tamox is pointing a gun at me, sometimes they point guns at each other, everyone had an itchy trigger finger ... who's going to get shot, who will be just winged and who will take the fatal bullet? NO ONE KNOWS!

My issue in all this is the non-compliance. Why does this happen? Are women stupid? Do they 'forget' to take pills? I believe that the side effects of this pill, whether or not researchers want to acknowledge them, can be quite devastating. I believe that taking a pill every day that makes you feel like shit is something that many women will eventually 'forget' to do. Understand also that when researchers do a trial, they have parameters and guidelines of what they will and won't, can and cannot accept as evidence. It is very likely that women have been telling researchers about side effects that the researchers either ignored or were not able to accept as hard data - because it was anecdotal and not proven in a laboratory (unless they were actively collecting anecdotal evidence).

I struggled with whether or not to take tamoxifen. I am not happy that I am. But I am. My solution was to take 1/2 a pill a day instead of 20mg. All the low dose trials I read about said that 1mg and 5 mg were effective. So I figure 10mg has to be. As I have said before, there is enough at 10mg to give me side effects. It has to be doing something!

My hope and the plan in the back of my mind is to maybe take tamox beyond 5 years, but maybe taper off to an even lower dose. Maybe take a 5 mg tablet every other day? Just to ping my system. I have no evidence whatsoever that this would do any good. But the research showing that 1 mg and 5 mg keep active and useful drug levels in a system gives me some hope that I can get long term benefits while making my discomfort and perhaps life threatening risks as low as possible.

But really, at the end of the day, it is all a gamble. A crap shoot. No guarantee. It's like a nightmare version of Los Vegas and you are forced to gamble with your life. Because that is what's on the line.

Shockedst48...your last answer is spot on. Be careful of statistics because they involve much more than numbers. The more responsive a cancer is to chemo, the better it works and the less responsive, the less benefit you would get from chemo which would mean the side effects wouldn't be worth it.

There appears to be some confusion regarding the study of Chirgwin (2016):

Chirgwin (2016), "Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence"

http://ascopubs.org/doi/full/10.1200/JCO.2015.63.8619

Here are my layperson comments.

The take-home message of Chirgwin is that endocrine therapy is beneficial and that persistence and compliance optimize outcomes as measured by disease-free survival. The results do NOT say that stopping early is worse than no treatment at all.

Re: "Also, I read on Breastcancer.org that women who start hormone therapy and then stop, for whatever reason, are at increased risk of having a recurrence. I don't know the exact mechanism for this, but here it is:"

http://www.breastcancer.org/research-news/not-taking-hormonal-tx-leads-to-more-recurrence

The italicized quote above might be read to suggest that shorter duration of treatment or missing doses worsens outcome versus no treatment at all, which is not the case and is not what was measured or reported. As explained in the feature, "A study has found that postmenopausal women who stop taking hormonal therapy early or skip doses are much more likely to have a breast cancer recurrence than women who take hormonal therapy as prescribed."

In other words, those who are not "persistent" (discontinued treatment early) are at increased risk relative to those who completed 54 o 60 months of treatment.

Those who are "non-compliant" (skipped a certain number doses as defined in the study) are at increased risk relative to those who were compliant as defined.

Importantly, those who receive shorter durations of therapy or with lower compliance during therapy are NOT at increased risk of recurrence relative to if they had not taken any treatment at all. For example, a placebo-controlled trial has demonstrated that two years of tamoxifen provided long-term reduction in breast cancer–related mortality in premenopausal patients with ER-positive breast cancer, compared with a systemically untreated control group.

Multiple clinical trials, including BIG 1-98, have demonstrated that various endocrine therapy regimens (5-years of Tamoxifen; or five years of an Aromatase Inhibitor; or five years of a "Switch" regimen) for early stage breast cancer can reduce local and distant recurrences as well as mortality.

Re: How were "persistence" and "compliance" measured?

Per the paper, "In the BIG 1-98 trial, full compliance consists of taking a dose of either letrozole 2.5 mg or tamoxifen 20 mg once per day, and full persistence consists of a duration of 54 to 60 months."

Compliance measurements had two components in this study: (1) compliance for a six-month drug pack (an 80% cut off for individual packs); and (2) a "global" compliance score which reflects compliance for multiple drug packs or how many of the six-month packs achieved 80% (a 90% cut-off when looking at how many packs achieved the 80% cut off).

Per the paper, "Compliance is defined as the consistency of taking protocol treatment. Treatment drug packs were distributed every 6 months. A patient was compliant for a drug pack if she took at least 80% of the pills during each 6-month interval, with no breaks of 7 days or more for any reason."

Per the paper, "To quantify compliance, a global score was created for each patient, defined as the percentage of drug packs where at least 80% of pills were taken with no breaks longer than 1 week. The complete analytic sample was divided into two groups: those with a [global] compliance score [greater than or equal to] 90% versus [less than] 90% of dispensed packs taken per protocol."

Re: "Your risk of suffering a disease free relapse can be anywhere from 35 - 60 % while on hormones whether you stop early or suffer for 5 years. To me this is much worse than the natural history with surgery alone."

This is not an accurate statement of the findings. The 35% and 56% are NOT "relapse risks" or rates of disease-free survival. Instead, the 35% and 56% values are derived from comparing outcomes between a group of patients who were persistent or a group of patients who were non-persistent as defined. These percentages reflect the amount by which disease-free survival is worsened by non-persistence relative to persistence.

The 61% is NOT a "relapse risk." Instead, the 61% value is derived from comparing outcomes between patients who were compliant versus those who were non-compliant as defined. The 61% value reflects the amount by which disease-free survival is worsened by non-compliance relative to compliance.

The authors concluded: "In this analysis, reduced persistence and reduced compliance were both associated with statistically significant increases in the risk of a DFS event." This means that disease-free survival is reduced by non-persistence (relative to persistence) or non-compliance (relative to compliant). Disease-free survival ("DFS") is optimized by persistence and compliance.

Here is what they found for PERSISTENCE:

"Letrozole monotherapy. Patients who received letrozole and stopped treatment early had a significantly increased hazard of a DFS event. HR was 1.35 (CI, 1.02 to 1.79) using a simple weighted Cox model (Wald x2 P = .04) and 1.45 (CI, 1.09 to 1.93) using a multivariable weighted model (Wald x2 P = .01)."

This says that for letrozole monotherapy, non-persistence ("stopped treatment early") increased the risk of suffering an event by 35% or 45% (Hazard ratio of 1.35 or 1.45, depending on modeling) compared to those who were persistent.

"Sequential therapy: tamoxifen-letrozole and letrozole-tamoxifen. Consistent with the results of the letrozole mono-therapy, the analysis of sequential treatments indicated that patients stopping treatment early had worse DFS than those who did not. The relative effect of treatment persistence was approximately the same for both sequences. The HRs of DFS (stopped early v not) in tamoxifen-letrozole were 1.46 (CI, 1.13 to 1.88) for the simple weighted model and 1.56 (CI, 1.21 to 2.01) for the multivariable model; in letrozole-tamoxifen, the HRs were 1.46 (CI, 1.12 to 1.87) and 1.57 (CI, 1.21 to 2.03) for the simple and multivariable models, respectively. (Fig 2)"

This says that the results for switch regimens (Tam-Let or Let-Tam) were similar to those with letrozole monotherapy, and non-persistence with switch regimens increased the risk of suffering an event by 46% or 56-57% (Hazard ratios of 1.46, 1.56 an 1.57) for those who "stopped early v not".

Again, these are NOT relapse risks, but reflect the worsening of disease-free survival due to non-persistence relative to persistence.

Here is what they found for COMPLIANCE:

"There were 51,218 drug-pack records in the database; 273 (0.5%) had missing compliance information (Table 1). Figure 3 summarizes the distribution of DFS events according to the compliance score dichotomized at 90%. Results from the Cox regression model show that among women who completed study therapy, there was a statistically significant 61% increase in the risk of a future DFS event for a compliance score of < 90% (HR, 1.61; CI, 1.08 to 2.38; P = .02)."

Again, the 61% is not a relapse risk, but reflects the worsening of disease-free survival due to non-compliance relative to compliance.

As the Discussion states:

"Because others have shown that longer durations of adjuvant tamoxifen result in superior outcomes, [4,9-11] it is not surprising that patients in the BIG 1-98 trial who ceased protocol-assigned endocrine treatment before completion experienced an increased risk of a DFS event."

This says endocrine therapy is beneficial, with longer durations of treatment providing improved outcomes. The findings of this study testing various 5-year regimens (or non-persistence with same) are consistent with these prior studies, and so it is not surprising that that those who stopped treatment early (non-persistent) in this trial had worse disease-free survival compared with those who were persistent.

They also comment: "What is of interest is the magnitude of the increase (35% to 56%) imparted by reduced persistence. The results of this analysis also suggest that a reduction in compliance translates into a DFS disadvantage, and it is the first to show that breast cancer outcomes relate to daily tablet compliance."

As is clear from the results quoted above the increased risk is relative to the risk with persistence. This says that the worsening of disease-free survival with non-persistence (relative to persistence) is not small and is material to outcomes. In addition, daily compliance is also important. The paper also provides information about some of the reasons for discontinuation or reduced day-to-day compliance, and notes that more effective management of side effects might improve persistence and compliance.

"in conclusion, this analysis shows that both components of adherence, persistence and compliance, are associated with DFS [disease-free survival]."

Thus, the take-home message of Chirgwin is that endocrine therapy is beneficial and that persistence and compliance optimize outcomes as measured by disease-free survival.

It is very easy for laypersons to misundertand clinical trial publications. If any outside information (papers or posts) influences individual decision-making about endocrine therapy, be certain to discuss the information your Medical Oncologist to discuss the study or information, confirm accuracy and currency of the information and your understanding of it, and applicability to your case.

BarredOwl

I think the misunderstanding is that the percentages are not rates of disease-free survival, but are hazard ratios reflecting the worsening of disease-free survival among those who are non-persistent relative to those who are persistent or among those who are non-compliant relative to those who are compliant.

Barred Owl, Thank you for your detailed analysis to clear up the confusion

Thank you for posting the definition of DFS for the purposes of this particular study (Chirgwin, 2016).

For an introduction to hazard ratios for laypersons, see page 12 of this pamphlet from Roche:

https://www.roche.com/dam/jcr:1d4d1b52-7e01-43ac-862f-17bb59912485/en/understanding_clinical_trials.pdf

It also includes general examples of various types of clinical trial endpoints; however, one should always check each study publication for the specific definitions of reported endpoints.

Again, I encourage all to discuss outside information that affects your thinking about treatment decisions with your team to ensure receipt of accurate, current, case-specific expert professional medical advice and soundly based treatment decisions.

BarredOwl

Hi marijen:

The short answer is I don't know.

Your first question seems to be asking about recurrence rate in those who take an AI versus those who receive no endocrine therapy. But in this study, no patients received placebo. They were not measuring the benefit of AI versus placebo. (I am not aware of any clinical trial of an Aromatase Inhibitor ("AI") as initial endocrine therapy (in first five years) for early breast cancer that has used placebo as comparator. Instead, AI or AI-containing "switch" regimens were compared to tamoxifen or to other AIs or to other AI-containing switch regimens. In contrast, Tamoxifen was compared to placebo.)

The analysis in Chirgwin (2016) was based on a subset of the post-menopausal women who participated in BIG 1-98 (6144 of them). They were randomly assigned to receive one of four treatments:

(1) tamoxifen for 5 years; or

(2) letrozole for 5 years; or

(3) tamoxifen (2 years) followed by letrozole (3 years); or

(4) letrozole (2 years) followed by tamoxifen (3 years).

As to your other questions relating to "recurrence", I could be wrong, but "recurrences" (as opposed to "progression" which was undefined) do not seem to have been separately reported in Chirgwin (2016). As noted by bosombuddy101, in this study, the clinical endpoint used was "DFS" which includes a number of different types of events, and is not limited to "recurrence":

Per the paper, "DFS is defined as the time from the date patients are randomly assigned to the date of the first proven invasive recurrence at any site, new invasive contralateral breast cancer, second nonbreast malignancy, or death from any cause." My layperson reading of "invasive recurrence at any site" would include local, regional and distant recurrences.

While the reported increased hazards in terms of disease-free survival were pretty large, the absolute differences in DFS may be more modest. For example, 5-year DFS rates are printed in Figure 2A for Letrozole (for greater than or equal to 36 months of Let or less than 36 months of Let).

Keep in mind that these DFS rates are averages for the group as a whole. However, the group is more diverse with respect to risk profile, and potential benefit is proportional to individual risk (greater risk translates into greater potential benefit). Because of this, patients with early stage invasive breast cancer considering initiating adjuvant endocrine therapy should request their medical oncologist provide case-specific estimates of the relevant risks and the potential benefits of endocrine therapy (versus no endocrine therapy) as part of a personalized risk benefit analysis, in which potential benefit is weighed against the risks of severe adverse effects.

In early stage invasive breast cancer, endocrine therapy can reduce the risk of mortality, the risk of distant (metastatic) recurrence, as well as the risks of loco-regional recurrence or new disease (a new primary in the same or contralateral breast). Patients should be sure to ask about the type of any risk estimate(s) provided by their medical oncologist. Write the information down and have your MO confirm the accuracy of your notes. For example, what type of recurrence risk is being discussed? (5-year? 10-year? Mortality? Distant recurrence? Other?)

BarredOwl

BarredOwl: Great clarifications!

I have now been on Tamoxifen for two weeks without any major side effects except a little bit of dry eyes. My Oncologist NP said if I was symptom free by the 3-4 weeks I would be very lucky