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Topic: Abemaciclib Verzenio for Stage IV

Forum: Stage IV/Metastatic Breast Cancer ONLY —

Please respect that this forum is for members with stage IV/metastatic breast cancer only. There is a separate forum for caregivers and friends: Caring for Someone with Stage 4 or Mets.

Posted on: Jan 1, 2018 05:03AM - edited Jun 18, 2018 12:19AM by zarovka

zarovka wrote:

Luckylegs and friends on Abemaciclib - I am bumping the Verzenio discussion in the hopes that more people have started abemaciclib. We need to get a community going. I have not started abemaciclib but it is on my short list. Like many I am very interested in how people do on this treatment do, both as a monotherapy and in combination with hormone suppression and other treatment. I am hoping that this thread can capture the experience of everyone on Abemaciclib in whatever combination. This is a very important treatment option that we all need to be evaluating.

I would expect more people on the drug given the significant advantages of abemaciclib over the first generation CDK 4/6 inhibitors. However, the FDA has approved abemaciclib for only limited indications. We have not established its use as a first line treatment nor as something to switch to from Ibrance. At the same time, they haven't made it clear that the drug can and should be used after Ibrance. As a result, the setting for using abemaciclib is supremely unclear.

I believe abemaciclib can be used either instead of or after palbo/ribo depending on whether you view abemiciclib as another class of drug or the same class of drug with significant improvement. One can make arguments for either strategy. If you've already done palbo/ribo, it is certainly worth trying abemaciclib. If you haven't done palbo/ribo, the current guideline that you start with the first generation CDK 4/6 is reasonable, but not necessary IMO. A lot depends on the side effect profile you can tolerate the best as the drugs have significant differences in side effects and also whether you are at risk of brain mets. Abemaciclib is better at crossing the blood brain barrier.

The following summary of abemaciclib data taken from a thread started by Constantine on Inspire. I moved his entire discussion from three posts because it's that good. Thank you Constantine.

ABEMACICLIB (VERZENIO)
Preliminary data from a phase I study of abemaciclib [SABCS 2014] in patients with five different tumor types including HR-positive metastatic breast cancer, with I note a median of seven prior systemic therapies (outliers out to 11 lines) found an objective response rate of 19% and a disease control rate (including stable disease (SD) under RECIST definition of >24 weeks of ) of 81% for HR-positive MBC patients. This Phase I study was expanded to evaluate abemaciclib plus fulvestrant in HR-positive MBC [ASCO 2014.] with patients having a median of four prior systemic therapies (and outliers out to the eight line), finding an objective response rate of 62% confirmed PRs.

A subsequent Phase I study [Tolaney et al, J Clin Oncol 2015;33(Suppl 1).] of abemaciclib in combination with different endocrine therapies for HR-positive MBC (median lines of treatment = 3, with outliers out to 8) demonstrated a disease control rate (CR + PR + SD) was 67% for those on abemaciclib + AI therapy, and 75% for those on abemaciclib + tamoxifen.

The phase II MONARCH-1 trial evaluated abemaciclib MONOTHERAPY in HR-positive, HER2-negative MBC patients with a median of 3 lines of prior therapy for advanced disease, including a median of 2 lines of chemotherapy (as opposed to endocrine or biological therapy) for advanced disease, yielding an objective response rate (ORR) of 17.4% and a clinical benefit rate (CBR) of 42.4%.

What's important to remember about MONARCH-1 is that many women in the study had already received multiple lines of endocrine treatment (median 3 - 5 previous lines in the metastatic setting, with outliers beyond that), developed resistance and were refractory to all of these treatments, AND progressed, many of whom also received chemotherapy, and these results were for MONOTHERAPY in a heavily pretreated population, which as I determined through examination of historical controls with any other agent achieves at best only 10 to 20% clinical benefit rates - half of that achieved by single-agent abemaciclib, and with responses of short duration.

Hence, the collective results of these trial, including MONARCH 1 (MONARCH-2 (with letrozole) and MONARCH-3 (with fulvestrant) are exceptionally exciting breakthrough in breast cancer therapeutics.

BREAKTHROUGH SURVIVAL
In addition, for me, the overall survival (OS) of these heavily pretreated MBC patients was 17 months, and that compares to historical control I review from all clinical trials to date, as significantly better than other survival results, which are usually are at best 13 months. Thus, consider that for the current champ, eribulin chemotherapy in this setting, the EMBRACE trial achieved a median overall survival (OS) was 13 months, we clearly have here a major advance and improvement in overall survival in the highly challenging later-line settings (past at least 3 lines of therapy).

HIGH TOLERABILITY
The major limiting constraint with all CDK4/6 inhibitors to date, like palbociclib (Ibrance), is their most common adverse effect, that of myelotoxicity via neutropenia (low WBC neutrophils), with palbociclib (Ibrance inducing some degree of neutropenia in over half of women on it, with associated dose interruptions and sometimes dose reductions, a toxicity that so fat from the available data seems to also afflict ribociclib.
But abemaciclib (Verzenio) evades a good deal of this because although strictly a CDK4/6 inhibitor, it is more specific in inhibiting CDK4, that is it is CDK4-selective, and myelotoxicity including neutropenia is primarily associated with CDK6, making the incidence of neutropenia on abemaciclib significantly lower and more manageable.

CLINICAL LESSONS ON ABEMACICLIB (VERZENIO)
And unlike palbociclib (Ibrance):

1. abemaciclib has strong single-agent activity in HR–positive MBC,
2. has durable response in later line settings,
3. a good tolerability profile with reduced neutropenia, and
4. to date the highest OS in these challenging heavily pretreated settings of any oncotherapeutic agent, whether endocrine therapy, chemotherapy, or biological therapy.

SOME NUANCES
1. The ESMO-reported MONARCH 3 Trial found an response rate of 48.2% for all patients, BUT for the subgroup of patients with measurable disease, a response rate (ORR) of 59.2%, these being the highest ever response rates achieved to date for ANY endocrine therapy in breast cancer.
2. And although data needs to mature further for survival outcomes, it is anticipated based on exploratory analyses that PFS will weigh in at an improvement of close to 12 months, again an extraordinary gain.
3. In addition, Verzenio was most effective in challenging populations like those with visceral metastases (especially liver) and those with rapidly recurrent (short disease-free-interval (DFS)) patients.
4. Finally, 16 patients across two of the three MONARCH trials were NED (complete response (CR)), likely to increase once the MONARCH-3 data matures, more still I anticipate when results are reported from the MONARCH PLUS and other trials.

DIARRHEA AND ITS MANAGEMENT
To put the adverse events into a bit of perspective, although it is true that with Verzenio, all-grade diarrhea was between 86 - 90%, yet serious (Grade 3+) incidence was 13 - 20% but this is aggregated across the trials, and note further that diarrhea incidence is concentrated during the first month, and more narrowly the MTO (median time to onset) of the first diarrhea event was 6 days, lasting a median duration of just 6 days for Grade 3. Furthermore, for the most recent MONARCH-3 RCT, grade 4 diarrhea was zero, and grade 3 diarrhea was just 9.5%.

An aggressive proactive regimen of:

- high-dose loperamide/Imodium (4 mg but NOT ever de-escalated down to 2mg (and up to 16 -32 mg daily);
- "Big Pink" (Petpto Bismol Extra Strength) used in "priming" mode (started on day 4 and also used for immediate relief during loperamide dosing;
- budesonide (Symbicort) for recalcitrant cases;
PLUS "adjunct interventions:
- high-dose probiotic (28 billion microorganism count in two divided doses), and
- electrolyte powder (most of the refractory diarrhea was analyzed to be secondary to disturbed microflora and electrolyte imbalances)
- at least 12 8 oz glasses of fluid daily, 8 of which should be electrolyte-enhanced

brought the rate of diarrhea-related drug omission or dose reduction down from 22% (MONARCH 1 and 2) to under 1 - 2% in the cohorts run by my research teams in India and the Middle East.
NOTE: We found that the adjunct interventions of Big Pink, high-dose probiotic, electrolyte rebalancing, and assured fluid intake were at least important as the conventional agents, and in cases that seem intractable, converted to success, given that therapy-driven diarrhea inevitably causes GI tract flora, and electrolyte, imbalances, aggravated by inadequate hydration. Also critical was "through-and-through" loperamide dosing: 4 mg at each episode, but NOT de-escalating - as current protocols do - down to 2 mg after first (that de-escalation regimen we found indifferently effective, with large numbers of failures.

And although not reported to date, I note that in the MONARCH 3 trials the incidence of ANY grade diarrhea dropped to just 2% (courtesy of data provided by Levi Garraway at Lilly).

ACTIVITY IN LOBULAR CARCINOMA
The trials largely fail to report to date differential invasive-type stats, but the impression from conversations with some principals is that lobular breast cancer subjects are unlikely to experience significant decrement, and I also extrapolate from some hints surrounding the PELOPS (Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study) Trial another CDK4/6 inhibitor palbociclib (Ibrance), as well as from some molecular considerations (the p27 gene is a key regulator of certain types of progression (G1 to S-phase) and it appears that lobular carcinomas tend to have higher p27 which in a complex way under contextual effects can have either positive or negative effects on phase progression), but we have to await sub-group analysis to report on this issue explicitly. I am cautiously confidant of little differential outcome, which I think may be confirmed across the general class of CDK inhibitors. In addition, both the lobular and the ductal groups appear to have benefited from the addition of palbociclib (Ibrance) in the PALOMA-/TRIO-18 Trial, but I note that the difference observed in PFS in that trial is likely to be an artificial artifact of the small patient in the subgroup with lobular carcinoma arm (n = 18/19) compared to n = 117 in the ductal subgroup, so this is a small sample size effect not a robust finding, an impression in agreement with that of the principal investigators (Richard Finn and UCLA and colleagues). As we learn more about lobular BC and abemaciclib in particular, I will offer further clarifications.

DEGREE OF DIFFERENCE - IBRANCE v VERZENIO
Given the dramatic 14-fold (!) greater CDK4 activity in abemaciclib (Verzenio) compared to palbociclib (Ibrance) and ribociclib (Kisqali), as MONARCH 3 lead author Angelo Di Leo has established and noted in interview, and other consequent fundamental molecular pathway differences, I view these as only shared-class (CDK), but therapeutically distinct, agents, more like the difference between third-generation capecitabine (Xeloda) versus first-generation 5-FU although these are both fluoropyrimidines.

So: More different than same as witness also the high degree of relative invariance of efficacy and durable response in later-line treatments for Verzenio compared to that of Ibrance (see my original posting, above). These differences are sufficient warrant for me to classify palbociclib (Ibrance) as a first-generation CDK inhibitor, and abemaciclib (Verzenio) as a second-generation CDK inhibitor. The devil - as always - is in the details.

CNS (BRAIN) ACTIVITY
We have preclinical data [Raub et al. Drug Metab Dispos. 2015] of the cross-BBB (blood-brain barrier) capability of Verzenio, as witness the remarkable benefit in GBM (glioblastoma, being even non-inferior to temozolomide (TMZ), the standard of care in cross-BBB activity, and this although not a human clinical, was an in vivo, not just in vitro, study. And the Dana-Farber JPBO human clinical trial (I3Y-MC-JPBO) under Sara Tolaney is investigating single-agent abemaciclib in patients with ER+/HER2+ brain metastases, where I fully expect clinically relevant CNS benefit to be confirmed, with first phase interim results reported in June at ASCO 2017 showing 2 patients (8.7%) out of 23 having confirmed partial response (PR).

I should point out that there has been some provisional data on palbociclib (Ibrance) having potential cross-BBB activity in brain metastasis, but I hasten to note that strong in vivo data show a 10-fold greater cross-BBB activity for abemaciclib than palbociclib, with abemaciclib brain levels being more efficient at substantially lower doses than palbociclib and also active for longer duration, and finally abemaciclib was active as monotherapy, palbociclib was not.

Finally, as to leptomeningeal metastases, no explicit data bears on this question directly, but as to date all agents active in brain metastases have also been active in leptomeningeal metastases, activity would be expected.

THE ISSUE OF SWITCHING
It remains an open question whether patients who have progressed on or after another CDK inhibitor like palbociclib (Ibrance) may derive significant benefit from continuance of CDK4/6 inhibition by using a following CDK inhibitor like abemaciclib (Verzenio), with many in-progress trials like TRINITI-120 (and NCT0185719319 and NCT0263204521, among others) exploring the issue. But there is some plausible extrapolation from some preclinical data which has suggested non–cross-resistance among CDK4/6 inhibitors. A Barts Cancer Institute study reported at SABCS 2016 found that some palbociclib(Ibrance)- and ribociclib(Kisqali)-resistant cell clones were sensitive to abemaciclib (Verzenio).

For patients now on Ibrance (or Kisqali) but who have NOT PROGRESSED , is it motivated to switch to abemaciclib (Verzenio)? This is an issue that needs to be thrashed about candidly with your oncology team and is a highly individual decision, but my own sense at this time is that it may be more optimal in the long run to stay the course, and consider abemaciclib (Verzenio) for recourse upon progression either off-label until the FDA expands its approval, or on one of the many abemaciclib (Verzenio) clinical trials available.

I would however entertain some specialized exceptions in which a switch now, off of Ibrance or Kisqali, onto abemaciclib (Verzenio), might be motivated; for example:

1. If a patient is experiencing repeated difficult-to-manage neutropenia, occasioning multiple drug interruptions or reductions (neutropenia being dramatically less with abemaciclib (Verzenio)), but the patient must weigh the associated countervailing issue of higher incidence - but still manageable I would argue - diarrhea on abemaciclib (Verzenio).
2. If a patient is in advanced later-line setting (say, more than 5 to 7 lines or so of treatment in the metastatic setting already completed), where it is suspected that abemaciclib (Verzenio) may be somewhat more consistent and durable in response and benefit in such challenging contexts. This is a difficult one to judgment-call, and I would tend to want to weigh each patient's circumstance and their complex treatment history and individual pathology to assist in the decision, since we have no hard data to be dispositive on this decision.

Yes, these are arguable and have to be intensively debated (as in a tumor board setting), but they are not wholly unreasonable. Outside of these exceptions, however, I do not see sufficient motivation to prematurely abandon Ibrance or Kisqali, as these have strong track records of efficacy and should be push to progression.

FDA APPROVAL

Abemaciclib is currently approved ...
1. as combination therapy with fulvestrant (Faslodex) for the treatment of women with HR+/HER2- advanced or metastatic breast cancer who experience disease progression AFTER ENDOCRINE therapy.

2. as monotherapy for the treatment of women with HR+/HER2- advanced or metastatic breast cancer who experience disease progression AFTER ENDOCRINE therapy AND prior CHEMOTHERAPY in the metastatic setting.

(Z) MO's have latitude to prescribe outside of these indications and there are strong arguments for doing so. My MO appears to have wide latitude to prescribe Abemaciclib and get insurance approval in other settings.

EXPANDED ACCESS:
Abemaciclib continues to be available through Lilly's attractive Expanded Access Program (EAP):
https://clinicaltrials.gov/ct2/show/NCT02792725?term=abemaciclib&rank=24
which is active and recruiting currently in several US locations (California, Florida, Minnesota, Missouri, Texas, and West Virginia), more being added. However that is for patients who have not as yet progressed on a previous CDK inhibitor like palbociclib (Ibrance), that is, for "switchers" who may want to explore the improved benefits of abemaciclib (Verzenio) over Ibrance (assuming the patient meet the other trial criteria); but not for patients who have already progressed on Ibrance.

RECHALLENGE

In several cases I have known, I counseled that although someone progressed on Ibrance, to reintroduce it after a hiatus of 3 - 6 months, and in many cases this washout appeared to resensitize the tumor cells to Ibrance, which upon re-introduction was newly effective. It is a variant of a trick I have counseled and seen working not infrequently with other agents like capecitabine (Xeloda) where after progression on it, I advised a trial on a new metronomic schedule (low-dose, continuous, daily, capecitabine) and seen again it newly effective despite previous progression, just by this shift I schedule (there is some provisional data for this, but not decisive). But these are beyond convention and reserved for highly special circumstances.

MARKERS THAT PREDICT RESPONSE TO CDK 4/6 INHIBITION
I am not convinced that there is any biomarker - protein or otherwise - that reliably identifies responsivity to CDK inhibitors, and Fabrice Andre of the Institut Gustave Roussy and colleagues, as reported in their presentation at ASCO 2017, were unable to identify any such biomarkers of response: neither Rb levels, p16 protein levels, Ki-67 cell proliferation, CDKN2A, CCND1, nor even ESR1 gene expression, all the usual suspects, and others, had any response-predictive value whatsoever. To date the only established biomarker for response to CDK4/6 inhibitors, remain hormone receptor positivity (HR+). Of course not everyone responds, but response rates remain historical high - and higher than any other treatment to date - and as long as one is HR+, one has the potential to benefit from a CDK inhibitor.

Constantine Kaniklidis
Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)
Oncology Reviewer, Current Oncology [journal]
Society for Integrative Oncology (SIO)
Member, European Association for Cancer Research (EACR)

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 26, 2018 12:20PM luce wrote:

any educated guesses as to if curcumin might interfere or interact with abemaciclib? what about metformin? (not taking either but considering both. there used to be something about metformin in the physicians' insert but i can't find it now.) thanks!

Curcumin also affects the way the liver uses two detoxifying enzymes called CYP1A2 and CYP2A6. It inhibits the action of the first enzyme but enhances the action of the second.

This basically means that curcumin potentially interacts with the same prescription drugs as grapefruit juice.



Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 26, 2018 03:03PM Husband11 wrote:

My wife is using both letrozole / ibrance and metformin, and getting good results from the letrozole / ibrance.

According to one researcher, Constantine Kanaklidis, there is no clinically significant interference between curcumin and letrozole, despite the theoretical overlap of cytochrome enzymes. It's not as strong an inhibitor as say grapefruit. Now that statement may only apply to ordinary curcumin, and not a preparation that dramatically increases the concentration of curcumin in the bloodstream, such as nanoparticle curcumin, liposomal curcumin, colloidal curcumin, etc.

That said, if I were going to use curcumin, I would opt for a potent version, such as liposomal, nanoparticle, etc, such a theracurmin in order to ensure that it is actually absorbed into the blood stream. As it produces much higher concentration of curcumin in the blood (60x). However, I personally wouldn't feel comfortable in jeopardizing the effectiveness of ibrance for not enough promise of reward. Despite the reassurances of Constantine Kanaklidis, the fact that curcumin, letrozole and ibrance all use cyp3A enzymes, just wouldn't leave me feeling comfortable. I don't see the strong enough evidence of the effectiveness of curcumin against cancer to jeopardize a treatment that does work.

Concerned husband Dx 2008, Left, Stage IIIB, Grade 3, 7/14 nodes, ER+/PR+, HER2- Dx 5/2016, Stage IV, metastasized to liver, ER+/PR+, HER2- Chemotherapy Xeloda (capecitabine) Targeted Therapy Ibrance (palbociclib) Chemotherapy Hormonal Therapy Femara (letrozole)
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Jan 26, 2018 03:18PM luce wrote:

husband 11: thanks for your great reply! it dovetails with my thoughts about curcumin: while nothing but the most-effective preparation would be worth taking (by the way, a baby aspirin is supposed to boost curcumin availability also), it may not be worth risking. the reason why i considered it is because i do seem to suffer from inflammation, as evidenced by a number of symptoms, not so much because of curcumin's anti-cancer effect. it didn't prevent my recurrence, so it's unlikely to help fight my very advanced and extensive cancer now.


Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 30, 2018 05:47PM Mostcapable wrote:

Reporting in after week finishing week two. So far, so good. I haven't had the diarrhea side effect at all. I do experience slight stomach discomfort from time to time. It's nothing that is not bearable. I've been on other therapies that are far worse. I won't get scans again until April. Just had bloodwork and my WBC is slightly off but only a few points off the norm. I asked the onco about time it take for response and she said there wasn't any data on that. Is anyone aware of any data that speaks to this?

Dx 10/8/2013, IDC, Right, Stage IV, metastasized to bone/liver, ER+/PR+, HER2- Hormonal Therapy 10/31/2013 Zoladex (goserelin) Hormonal Therapy 11/1/2013 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Hormonal Therapy 7/31/2015 Arimidex (anastrozole) Hormonal Therapy 1/8/2017 Faslodex (fulvestrant) Targeted Therapy 1/8/2017 Ibrance (palbociclib) Targeted Therapy 1/8/2017 Targeted Therapy 1/13/2018 Hormonal Therapy 1/14/2018 Femara (letrozole) Hormonal Therapy Aromasin (exemestane) Targeted Therapy Afinitor (everolimus)
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Jan 30, 2018 08:08PM zarovka wrote:

For CDK 4/6 inhibitors as a class it takes up to 3 months to see a response and they can keep driving the cancer back for 12-18 months. Its a slow process. Not like chemo. This is the data for Ibrance and Ribociclib/kisquali. There is no practical reason why abemaciclib should be different or why your onc should be so cagey. But they are like that.

>Z<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 30, 2018 09:56PM - edited Jan 30, 2018 09:57PM by luce

all right. i have been taking abemaciclib for three weeks now (monotherapy, 200mg) and side effects kicked in after first week and are horrific and haven't abated: i have watery diarrhea 100% of the time. unable to leave the house. painful cramps, too. extreme fatigue. have been taking electrolytes (of my own making) but not imodium since i have had no one to go to the pharmacy and pick it up for me.

any advice? did the diarrhea stop for anyone after, say, the first month? that's what some of the studies reported. i could reduce the dose but would of course like the best possible chance of the best possible effect.

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 30, 2018 10:30PM zarovka wrote:

lifting from constantine's comments ... "diarrhea incidence is concentrated during the first month, and more narrowly the MTO (median time to onset) of the first diarrhea event was 6 days, lasting a median duration of just 6 days for Grade 3 diarrhea." sounds like you have grade 4 diarrhea so median duration is going to be longer, probably. but it does end.

however, dropping down the dose to reduce the side effects, at least for a period, may not reduce efficacy. they establish the doses of the drugs based on maximum tolerated dose, not efficacy, believe it or not. efficacy does not necessarily increase with dose. IMO we're getting doses that are too high much of the time and side effects have a real and negative effect on outcomes.

i'm concerned.

>Z<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 30, 2018 10:36PM - edited Jan 30, 2018 10:40PM by luce

zarovka: yes, thanks for the reminder about dosage. good point. i knew that about tamoxifen. i had asked for a reduced dose a week ago but my oncologist's office forgot to put the order in, apparently. i re-requested today and am expecting it by thursday. i'll drop the dose down to 150 mg, at least for a while.

yes, grade 4, and for 13 days so far. how much longer does grade 4 take to resolve, do you think? i am feeling like i am dying. thing is, that might actually be because i am actually dying, and not from abemaciclib. my lung symptoms are getting worse and worse.


Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 30, 2018 11:05PM Moissy wrote:

Luce - Piggybacking onto Z's info, below is a specific recommendation about diarrhea treatment while on abemaciclib from a post by Constantine (user name Edgerider on Inspire.com.) Sorry, I'm on my phone and can't link directly right now.

I would urge you to get Imodium immediately to control the symptoms. Constantine says it is manageable and I am worried that the diarrhea is weakening you. Could a pharmacy near you possibly deliver? Please do not wait for this to go away on its own. There is no reason for you to be in such misery. We all want to see you strong so that abemaciclib has a chance to work for you.

Moissy

Below is directly quoted from his post:

An aggressive proactive regimen of:

- high-dose loperamide/Imodium (4 mg but NOT ever de-escalated down to 2mg (and up to 16 -32 mg daily);
- "Big Pink" (Petpto Bismol Extra Strength) used in "priming" mode (started on day 4 and also used for immediate relief during loperamide dosing;
- budesonide (Symbicort) for recalcitrant cases;
PLUS "adjunct interventions:
- high-dose probiotic (28 billion microorganism count in two divided doses), and
- electrolyte powder (most of the refractory diarrhea was analyzed to be secondary to disturbed microflora and electrolyte imbalances)
- at least 12 8 oz glasses of fluid daily, 8 of which should be electrolyte-enhanced

brought the rate of diarrhea-related drug omission or dose reduction down from 22% (MONARCH 1 and 2) to under 1 - 2% in the cohorts run by my research teams in India and the Middle East.
NOTE: We found that the adjunct interventions of Big Pink, high-dose probiotic, electrolyte rebalancing, and assured fluid intake were at least important as the conventional agents, and in cases that seem intractable, converted to success, given that therapy-driven diarrhea inevitably causes GI tract flora, and electrolyte, imbalances, aggravated by inadequate hydration. Also critical was "through-and-through" loperamide dosing: 4 mg at each episode, but NOT de-escalating - as current protocols do - down to 2 mg after first (that de-escalation regimen we found indifferently effective, with large numbers of failures.

And although not reported to date, I note that in the MONARCH 3 trials the incidence of ANY grade diarrhea dropped to just 2% (courtesy of data provided by Levi Garraway at Lilly).


Dx 2004, IDC, 6cm+, Grade 2, 0/1 nodes, ER+, HER2- Dx 2015, Stage IV, ER+/PR+, HER2-
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Jan 30, 2018 11:21PM zarovka wrote:

oh luce. sending waves of strength.

i am concerned also that you can't get immodium. it suggests a lack of a support network that is not going to work even medium term. i hope you can figure out how to get support during periods when you are really beaten up. this advice is coming from the person who did not ask for assistance transferring gates at DFW when I had a high fever and could barely walk. i am not prepared to own that I need help, myself. but as an outside observer, i can say that you need immodium and you will need other things until this diarrhea lightens up. there are angel groups and all kinds of horribly kind people ready to help. your doctor can connect you with the groups that do this.

when i am in pain or symptomatic in any way, i can't keep the dark thoughts away. a little hair loss, and I am blubbering pile of tears. in fact the dark thoughts haven't correlated with outcomes, just with pain and symptoms. i do know how you feel. when do we stop trying to optimize and just let go? NOT YET. get some sleep and call a cancer support group in the AM, please.

>Z<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 30, 2018 11:55PM luce wrote:

moissy and zarovka:

thanks for caring and advice!

well, i am single since my boyfriend broke up with my a month ago, and the three friends who usually help me all happen to be on vacation this week. another friend just brought me the immodium but he had been out of town until now. just bad timing; i usually have some support. and, yes, i also have a hard time asking for help, or accepting it, in general.

(while diarrhea is annoying and weakening, my main problem IS in my lungs; my oxygen saturation keeps dropping even on supplemental oxygen. i get out of breath standing still at this point. i actually think i am not thinking catastrophically at all but rather too much in denial still. i am pretty sure my oncologists think i only have weeks, if that. i am just too chicken to ask. but they approved my death-with-dignity drugs months ago. you can only get those if your prognosis is less than 6 months.)

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 31, 2018 07:06AM zarovka wrote:

stay in the moment. focus on doing the best you can to care for yourself. it really doesn't matter what anyone thinks. nobody knows.

with you ...

>Z<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 31, 2018 08:39AM Moissy wrote:

Luce - I hope you will start to feel better soon.

This site has many personal stories of women being told they had such and such an amount of time to live only to live many years longer. I truly believe that if your doctor did not think this treatment had a chance of helping you, he or she wouldn't have prescribed it.

I'm sorry about your boyfriend. That alone must be really hard. With this disease, all of us have had dark moments when we project negatively into the future. But when a treatment starts WORKING, it is possible to regain hope that you may not feel right now.

Hugs to you.

Dx 2004, IDC, 6cm+, Grade 2, 0/1 nodes, ER+, HER2- Dx 2015, Stage IV, ER+/PR+, HER2-
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Jan 31, 2018 08:41AM Moissy wrote:

Z- Hope you are feeling better as well after your harrowing airport excursion and new treatments.

Dx 2004, IDC, 6cm+, Grade 2, 0/1 nodes, ER+, HER2- Dx 2015, Stage IV, ER+/PR+, HER2-
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Jan 31, 2018 09:53PM Mostcapable wrote:

God bless you Luce! I pray the Imodium helps. Z and Moissy - you are angels. Blessings to you both. Thank you for sharing the info Z

Dx 10/8/2013, IDC, Right, Stage IV, metastasized to bone/liver, ER+/PR+, HER2- Hormonal Therapy 10/31/2013 Zoladex (goserelin) Hormonal Therapy 11/1/2013 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Hormonal Therapy 7/31/2015 Arimidex (anastrozole) Hormonal Therapy 1/8/2017 Faslodex (fulvestrant) Targeted Therapy 1/8/2017 Ibrance (palbociclib) Targeted Therapy 1/8/2017 Targeted Therapy 1/13/2018 Hormonal Therapy 1/14/2018 Femara (letrozole) Hormonal Therapy Aromasin (exemestane) Targeted Therapy Afinitor (everolimus)
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Jan 31, 2018 10:30PM - edited Jan 31, 2018 10:37PM by luce

reporting on imodium: took a total of 8 mg today and so far, no diarrhea (but i sometimes skip a day and have no bowel movements at all, simply because i am too empty, i think) but i can barely stay awake! i had to take a 3-hour nap shortly after taking the first 4 mgs. and i have had heavy eyes all day. this is really unpleasant, as i was hoping to be less fatigued with less diarrhea. profound fatigue is one of the symptoms of dying, so feeling this tired and weak is really disconcerting to me at this point, and not an acceptable side effect (if caused by imodium). i am almost certain imodium, an opioid, is the reason, though.

therefore, i think an abemaciclib dose-reduction (to 150 mg; i take it as monotherapy, so am on 200mg) makes sense for me. hopefully, the diarrhea will subside on a lower dose. also, i have had mild but persistent nausea on abemaciclib, and i don't like it. i am already skinny, and nausea goes hand in hand with inappetence. more nausea and even less appetite today, so i am suspecting imodium contributes to that.

anyone else got that tired from imodium? did anyone tolerate abemaciclib much better after a dose reduction?


Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Feb 1, 2018 01:29AM Cure-ious wrote:

Hi Luce- Late to the discussion, but you may be wiped out from all of the GI problems alone, let alone the difficulty breathing and all the stress.

Can you let us know the treatments you have already had for MBC, and what response and SEs you had from them?

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Feb 1, 2018 02:37AM Liwi wrote:

Hi Luce. Have you tried any breathing techniques to get your stress level down? GI issues really escalate my stress level and breathing. The easiest technique I use is to breath in to a count of 6, then exhale for 8 to try to breath fully and slow down my breathing which helps my stress. I do it lying down or sitting for several minutes. I also concentrate on bringing in good air and expelling any toxins. I’m guessing you fatigue may be from the drugs, not being able to eat stressand being dehydrated.

I hope tomorrow is a better day for you.

Dx 9/2014, ILC, Left, 4cm, Stage IIB, Grade 2, ER+/PR+, HER2- Chemotherapy 10/23/2014 AC + T (Taxol) Dx 4/2015, ILC, Left, 6cm+, Stage IIIA, Grade 2, 3/3 nodes, ER+/PR+, HER2- Surgery 4/1/2015 Lumpectomy: Left; Lymph node removal: Sentinel Hormonal Therapy 4/19/2015 Arimidex (anastrozole) Radiation Therapy 5/6/2015 Dx 7/2017, ILC, Stage IV, metastasized to liver, ER+/PR+, HER2- Hormonal Therapy 8/9/2017 Faslodex (fulvestrant) Targeted Therapy 8/10/2017 Ibrance (palbociclib) Dx 8/1/2018, ILC, Stage IV, metastasized to other, ER+/PR-, HER2- Chemotherapy Doxil (doxorubicin)
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Feb 1, 2018 01:12PM - edited Feb 1, 2018 01:17PM by luce

Liwi: Thanks for your kind suggestion. I am familiar with that breathing technique (and many more: I happen to be a certified yoga instructor) but my symptoms are not due to stress. And, sadly, breathing exercises and -meditations don't work for me anymore: I have extensive tumor growths obstructing my lung parenchyma.

Cure-ious: No other standard-of-care therapies apart from abemaciclib. For quality-of-life reasons, I am neither interested in chemo- nor endocrine therapy.

I feel this increased fatigue is distinctly linked to Imodium, so was wondering if anyone had experienced that also. I guess it is too early to ask if anyone has had a response to reduced-dose abemaciclib!

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Feb 1, 2018 03:33PM blainejennifer wrote:

Luce,

So happy to hear that you got the immodium! It makes me very tired too. If I take the full dose, I get the "can't move my limbs" kind of tired. Not sleepy, just exhausted.

Keep the fluids coming. Have you done a pinch test on your skin to make sure you aren't dehydrated? I'm sure you know it: you pinch the thin skin on the back of your hand, and if the skin retains the fold, get some fluids in you.

Jennifer

ER/PR+, HER2-, Grade 3. Stage 4, July 2012. Currently on Gemzar/Carboplatin Dx 5/2006, IDC, 4cm, Stage IIB, Grade 3, 4/12 nodes, ER+/PR+, HER2- Dx 3/2012, IDC, Stage IV, 4/12 nodes, ER+/PR+, HER2- Chemotherapy 6/27/2012 Taxol (paclitaxel) Hormonal Therapy 6/4/2013 Faslodex (fulvestrant) Chemotherapy 6/30/2014 Xeloda (capecitabine) Hormonal Therapy 8/14/2015 Femara (letrozole) Chemotherapy 1/31/2016 Halaven (eribulin) Chemotherapy 8/30/2016 CMF Chemotherapy 10/31/2016 Halaven (eribulin) Chemotherapy Carboplatin (Paraplatin), Gemzar (gemcitabine)
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Feb 1, 2018 03:40PM luce wrote:

blainejennifer: thanks for sharing your experience with imodium and fatigue! i knew it wasn't just me: apparently, it is a well-known side-effect amongst people with irritable bowel syndrome who take immodium. i, too, find it almost impossible to move: i have to psych myself up just to stand up, and i can't even sit up straight on this stuff. and in me, it definitely causes sleepiness and heavy eyelids.

yep, i have been pinching myself and am not excessively dehydrated. i have been very good about electrolye and fluid intake.

this fatigue is different from diarrhea fatigue: it feels spacy and drug-induced. i must be rather sensitive to the opiod effect of imodium. i mean, why wouldn't it affect some people strongly even if it "mostly stays in the gut"?--there is the very strong gut-brain connection via the vagus nerve, etc.

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Feb 1, 2018 08:06PM luce wrote:

here's what my oncologist replied regarding dose-reduction and efficacy:

Doses are initially found in early trials based on tolerability, but historically that has correlated with efficacy. For some of the new drugs we are finding efficacy at lower doses, whether equivalent or not to full dose is unknown for most. Palbociclib has it seems similar efficacy at lower doses but that was in patients who started high dose and required reductions

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Feb 1, 2018 08:40PM luce wrote:

so, on imodium, i can barely eat. i have zero appetite today and increased nausea. also, i haven't had a bowel movement in the two days i have taken it, and i DID (against constantine's advice) taper down to 2mg after the initial dose because i anticipated constipation. in fact, i only had 2mg of imodium today, because i could only get myself to eat once. while OF COURSE, those symptoms--nausea, inappetence--could be and have been symptoms of my condition or side effects from abemaciclib (which also makes me nauseous), all have been so much more pronounced since imodium, so i strongly suspect that. this is becoming one of those solution-worse-than-problem situations. i really hope i can tolerate abemaciclib at the reduced dose (expecting delivery tomorrow), because throwing more medications at the problem is not working for me.

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Feb 1, 2018 08:57PM zarovka wrote:

luce - remember that the diarrhea doesn't persist, generally. it's a matter of getting through it.

hugs and support. this is very tough.

>Z<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Feb 1, 2018 08:59PM Moissy wrote:

MostCapable - Thanks for the update! It’s great hearing front line experience on this protocol since it’s so new.

Luce - Glad to hear the D has subsided & your reduced dose is on the way. Hope that you will find the right combo that minimizes side effects

Dx 2004, IDC, 6cm+, Grade 2, 0/1 nodes, ER+, HER2- Dx 2015, Stage IV, ER+/PR+, HER2-
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Feb 1, 2018 09:40PM Liwi wrote:

Luce I hope your side effects start diminishing soon. Also that the Abemaciclib works for you. Sorry you are going through this difficult time.

Dx 9/2014, ILC, Left, 4cm, Stage IIB, Grade 2, ER+/PR+, HER2- Chemotherapy 10/23/2014 AC + T (Taxol) Dx 4/2015, ILC, Left, 6cm+, Stage IIIA, Grade 2, 3/3 nodes, ER+/PR+, HER2- Surgery 4/1/2015 Lumpectomy: Left; Lymph node removal: Sentinel Hormonal Therapy 4/19/2015 Arimidex (anastrozole) Radiation Therapy 5/6/2015 Dx 7/2017, ILC, Stage IV, metastasized to liver, ER+/PR+, HER2- Hormonal Therapy 8/9/2017 Faslodex (fulvestrant) Targeted Therapy 8/10/2017 Ibrance (palbociclib) Dx 8/1/2018, ILC, Stage IV, metastasized to other, ER+/PR-, HER2- Chemotherapy Doxil (doxorubicin)
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Feb 1, 2018 11:18PM AnimalCrackers wrote:

Luce - I know you don’t want to throw more drugs into the mix but zophran has been very helpful for me when I get nausea. Just a thought. Also I have had to use Imodium recently but I did not feel tired from it. I only needed it a couple times so that’s not much to go on I guess.

Hope you feel better.

Cathy, Diagnosed de novo bone mets June 2014 at age 52. Progression to Liver 2017. Progression to bone mets Sept. 2018. Bisphoshonate (Zometa) infusions every 3 months. Participated in 2 clinical trials, including an AKT1 inhibitor. Dx 6/23/2014, IDC, Left, 4cm, Stage IV, metastasized to bone, mets, ER+/PR+, HER2- Hormonal Therapy 6/23/2014 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Hormonal Therapy 1/5/2016 Femara (letrozole) Targeted Therapy 1/5/2016 Ibrance (palbociclib) Dx 4/2017, IDC, metastasized to liver, ER+/PR+, HER2- Hormonal Therapy 5/18/2017 Targeted Therapy 5/18/2017 Kisqali Hormonal Therapy 12/19/2017 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Targeted Therapy 12/19/2017 Dx 8/20/2018, IDC, Stage IV, metastasized to bone Radiation Therapy 8/20/2018 External: Bone Chemotherapy Taxol (paclitaxel) Surgery
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Feb 2, 2018 12:42AM JFL wrote:

Luce, I had no idea Imodium was in the opiod family. I googled it after reading your post. Disturbing!!!

Chart your own course. Dx at 30. Dx with mets at 38 while pregnant - extensive liver & bone involvement. Currently on Enhertu & XGeva. ER+/PR+, HER2-low (IHC equivocal, +2/FISH negative). Y90 liver radioembolization in 2018. Dx 9/2006, IDC, Right, 1cm, Stage IIB, Grade 3, 1/16 nodes, ER+/PR+, HER2- (FISH) Surgery 9/22/2006 Mastectomy: Left, Right Chemotherapy 11/6/2006 Adriamycin (doxorubicin), Cytoxan (cyclophosphamide), Taxotere (docetaxel) Hormonal Therapy 3/15/2007 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Dx 12/2014, IDC, Stage IV, metastasized to bone/liver/other, Grade 3, ER+/PR-, HER2- Surgery 12/26/2014 Prophylactic ovary removal Hormonal Therapy 12/26/2014 Aromasin (exemestane), Faslodex (fulvestrant) Targeted Therapy 6/18/2015 Ibrance (palbociclib) Chemotherapy 3/10/2016 Xeloda (capecitabine) Hormonal Therapy 5/14/2017 Aromasin (exemestane) Targeted Therapy 5/14/2017 Afinitor (everolimus) Chemotherapy 8/18/2017 Abraxane (albumin-bound or nab-paclitaxel) Chemotherapy 3/23/2018 Doxil (doxorubicin) Chemotherapy 4/26/2019 Navelbine (vinorelbine) Hormonal Therapy 4/26/2019 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Chemotherapy 11/27/2019 Gemzar (gemcitabine) Hormonal Therapy 8/25/2020 Faslodex (fulvestrant) Targeted Therapy 8/25/2020 Piqray (alpelisib) Targeted Therapy 10/2/2020 Enhertu (fam-trastuzumab deruxtecan-nxki)
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Feb 3, 2018 01:19AM spicedlife wrote:

I've just barely caught up with reading this thread since I was last online. It is midnight (I know it's way to late to still be up but since getting bone mets my ability to sleep has gone out the window.) Sorry y'all but I don't know how to take the bold font off.

I start my second 28 day cycle of verzenio tomorrow. I have been back at work for two weeks and other than fatigue and nausea (which is easily controlled) I think I am doing great. I sat at home for two weeks waiting to get the side effects that I had read about verzenio and other than one short bout of diarrea I am good.

My problem other than not sleeping well is the dry skin. I have always had horriibly dry skin but now it is ridiculous. I haven't found a solution yet.

I'm going to sleep now but hope to join in the discussion tomorrow. I want to tell you all my adventures of the first 28 day cycle of this drug.

Love, Jenny

Surgery 3/5/2012 Lumpectomy: Right; Lymph node removal: Right, Sentinel Surgery 4/16/2012 Lymph node removal: Right, Underarm/Axillary; Mastectomy: Right; Prophylactic mastectomy: Left; Reconstruction (left): DIEP flap; Reconstruction (right): DIEP flap Chemotherapy 6/4/2012 Cytoxan (cyclophosphamide), Taxotere (docetaxel) Hormonal Therapy 10/8/2012 Femara (letrozole) Surgery 11/5/2012 Reconstruction (left): DIEP flap, Nipple reconstruction; Reconstruction (right): DIEP flap, Nipple reconstruction Surgery 3/16/2013 Reconstruction (left): DIEP flap, Nipple reconstruction; Reconstruction (right): DIEP flap, Nipple reconstruction Dx 11/30/2017, IDC, Stage IV, metastasized to bone, Grade 2, 1/15 nodes, ER+/PR+, HER2- (FISH)
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Feb 3, 2018 07:28PM zarovka wrote:

Welcome spicedlife - We want to hear everything!

>Z<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)

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