Counterintuitive, estradiol as treatment

[Nguyen]

Hello,

We partially dodge a bullet last night, and at risk of jinxing my wife (knock on wood many times) I post this message, since there are useful info that others need to know. Since 09/2009 my wife has been on 6mg of estradiol daily (see below abstract). This counter intuitive treatment is working, though there are two major surprises. She had been in chemo induced menopause since 1998, yet 3 months after starting estradiol, her period has came back. Though we knew that estradiol would cause some thickening of the uterus, we were surprise to find that it has thicken to 23mm (about 5mm for woman in menopause) after only 6 months. Fortunately, last night uterine biopsy result is negative, though there are polyps. We plan to have a hysterectomy as soon as possible. So if you plan to use estradiol as a form of treatment, perhaps disccussing with your doc about removing the uterus first would be wise. Since this is a counter-intuitive treatment, below is how Linda's body respond to the treatment.

3/08: CA27.29: 63 ; Estradiol level: 7
9/09: CA27.29: 86 ; Starting estradiol pills daily at 6mg
10/09: CA27.29: 85; estradiol level 12
11/09: CA27.29: 88; estradiol level 512
12/09: CA27.29: 63; no longer check estradiol level
01/10: CA27.29: 53
02/10: CA27.29: 51
03/10: CA27.29: 55 I've started to worry
04/10: CA27.29: 35 This significant drop is a bit puzzling

Nguyen

Linda's treatment history:
09-2009 - current: Herceptin and estradiol
09/2008 - 09/2009: Herceptin, Fulvestrant, Femara
03/2008 - 09/2008: Herceptin, Exemestane, Oophorectomy
01/2005 - 03/2008: Herceptin (readded) and Femara
07/2004: It returned again via several small nodules in the lung
10/2002: NED (via CT and CA27.29)!
10/2001 - 01/2005: Femara, (Fosamax)
12/2000 - 10/2001: Herceptin and Navelbine
12/2000: lung metastatic was diagnosed (a few small nodules)
02/1998 - 12/2000: Daily Tamoxifen
05/1997 - 04/1998: Modified Radical Mastectomy, many many cycles of chemo regiments (CAF,Taxol, Carpoplatin, Thiotepa, Navelbine, Taxotere), including HDC, and radiation
05/1997: First diagnosed with BC stage 3A, ER+, PR+, HER2 +, poorly differetiated, nuclear grade 3.

Abstract:

A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.

Ellis MJ, Dehdahti F, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Jeffe DB, Gao F, Fleming G, Silverman P, Dickler M, Carey L, Marcom PK Siteman Cancer Center, St Louis; University of Chicago, Chicago; Case Western Reserve University, Cleveland; MSKCC, New York; UNC, Chapel Hill; Duke University, Durham

Rationale: It has been postulated that aromatase inhibitor (AI) therapy may sensitize ER+ breast cancer to lower doses of estrogen therapy as second-line endocrine treatment for advanced breast cancer (ABC). We therefore conducted a randomized trial of 30mg generic estradiol daily (10 mg t.i.d.- recommended dose) versus 6 mg (2 mg t.i.d - experimental dose).
Materials and Methods: Major eligibility: Postmenopausal ER+ ABC treated with an AI with 24+ wks progression free survival, or relapse after 2+ yrs of adjuvant AI; RECIST measureable non-bone metastases or WHO assessable bone lesions, with elevated tumor markers >2X ULN. Major exclusions: History venous thrombosis, heart disease, uncontrolled hypercalcemia and fulvestant in the last 12 months. FDG PET scans were conducted at baseline and after 24 hours to assess metabolic flare as a predictor of response (pre-defined as a 12% increase in FDG uptake).
Results: Sixty-six patients were enrolled (82% White, 15% Black); mean age 59 years, range 36-84. 34 received 6 mg and 32 received 30 mg. Estradiol levels will be provided at the meeting. There were more patients experiencing grade 3+ SAE on the 30 mg arm versus the 6 mg arm (11 vs. 4; P=0.06) with one venous thrombosis on each arm. There was no difference in total FACT-B QOL scores at one month by treatment arm, QOL decline was associated with more severe estrogen side effects, especially amongst patients on the 30 mg arm (P=0.006). Uterine bleeding was successfully controlled with intermittent progestin therapy. Clinical benefit rates (stable disease at least 24 weeks plus response - intent to treat population) were 25% (CI: 15-37%, 1PR and 7SD out of 32) on the 30 mg arm and 29% (CI: 19-42%, 3PR and 7SD out of 34) on the 6 mg arm. Patients with clinical benefit to estradiol could be retreated with original AI after progression and to date one PR out of three patients with repeat AI therapy noted. There were 44 patients evaluable for the interaction between PET -flare and response. Flare was seen in all responders (3/3), 9 of 13 patients with SD and only 3 of 30 patients with PD (p<0.0001). PPV for PET flare was therefore 12/15 (80%, CI: 61-92%) and NPV 27/31 (87%, CI: 76-94%).
Conclusions: The Protocol Review and Monitoring Committee closed the 30 mg arm early after they concluded that the 6 mg arm was as effective as the 30 mg arm with greater safety. We therefore recommend 6 mg as the appropriate dose for the palliative treatment of advanced ER+ breast cancer. FDG PET flare can be used to identify patients who have a high chance of clinical benefit.
Supported by an AVON NCI Partners in Progress Award: Grant # P30 CA091842-S4.

Thursday, December 11, 2008 10:30 AM

"...Dr. Ellis presented two cases to illustrate how estradiol therapy could restore aromatase sensitivity. One patient had a partial response for 48 weeks with 6 mg of estradiol, followed by another partial response lasting 36 weeks with an aromatase inhibitor, followed by a 12-week partial response with estradiol. The patient has since responded to treatment with fulvestrant (Faslodex)...."

[Rich66]

It's great to someone benefitting from this low toxicity approach! Sounds like your onc is working the her2 crosstalk and estrogen as therapy simultaneously. Very cool. It seems many oncs overlook the potential of ER issues in metastatic BC.
Did the onc give anything other than hunch as reason to try the inverted endocrine approach? Seems like the hard part would be administering meds that will likely feed or inhibit the cancer. Wish there was a simple way to monitor the ER behavior to know when to make the switch. Seems like a lot of mileage could be had if therapy could intelligently alternate between inhibiting and adding Estrogen. There is also suggestion that intermittent use of Femara can be helpful. Again..the hard part is deciding when to pull the plug and plug it back in.

But all this is even more enticing since long term Herceptin can seemingly give rise to ER positivity in previously ER neg tumors. This potentially makes the issue relevant to more than the small % of pathology based Her2/ER+ patients.

[Hopeful]

Nguyen,

I have been reading about the type of therapy your wife is having for several years. Thank you so much for your post. I am happy to read about someone achieving success with this therapy.

Continued best of luck to you and your wife,

Hopeful

[Nguyen]

Thank you Hopeful!

Hi Rich66, the oncologist usually pushed for chemo, I pushed for something milder and saved chemo as last resort. Though at time I got panic. After fulvestrant failed her, I was thinking of Laptinib and Herceptin, or Herceptin-DM1, or estradiol therapy (from Dr. Ellis's latest trial) as the next step. We decided on estradiol due to the "low" tumour burden and perhaps slow growth, the low toxicity and the possibilty of reusing in AI. I was very nervous, especially when the doc did not want to do the two fdg-pet scan to get early indication of if it'd work, I couldn't twist his arm since my wife didn't really want to do the fdg-pet scans either due to fear of additional radiation. I was very nervous for a long time, what if it didn't work, yet made the things grew faster, or worse yet started another site. After finding that estradiol had already been used "successfully" some 30 years ago, and that there're two patients (of another doc) in the clinic on the same treatment now, and agreeing on monthly CA27.29, we went ahead for it. I guess I'm still nervous since when it resumes growing, would it grow faster? Why fulvestrant was a major exclusion factor in the trial?

[Hopeful]

Nguyen,

I think I can answer your question. Fulvestrant has a different method of action than the other hormonals. SERMs, like Tamoxifen, use a weaker estrogen than the body's own to bind to the estrogen receptors on the cells. AI's prevent the body from transforming androgens into ER, and thereby also deprive the ER receptors on the cells surfaces from binding ER circulating in the body. In contrast, Fulvestrant irreversibly erodes the ER receptors on the cells surface, so that ER is unable to bind to the cells. If you are giving high doses of ER as therapy, the therapy will only work if there are receptors on the cells for it to bind to. Since not all of the cells with ER receptors regenerate quickly, my assumption is that the researchers running the study wanted to assure themselves that the patients in the study had estrogen receptors on the cells for the estrogen therapy to bind to. Otherwise, it wouldn't work.

Hopeful

[Nguyen]

Thank you Hopeful, your explanation makes sense. Although it's puzzling in my wife case, since she was on Fulvestrant just before starting estradiol. I emailed Dr. Ellis but of course the chance of hearing back is very slim.

Nguyen

[Rich66]

My this all gets complicated. I hadn't factored in Fulvestrant destroying the receptors that adding Estradiol woudl depend on. Although...if there is growth after Fulvestrant is stopped, there might be new estrogen receptors on the new cells.

"I was very nervous, especially when the doc did not want to do the two fdg-pet scan to get early indication of if it'd work"

Another interesting consideration. Especially since it can take months for endocrine therapy to show "shrinkage" on a CT. But..I think I saw somewhere that endocrine therapy can induce an initial flare:

Video clip from makers of Faslodex on hormonal aspects of BC:
http://www.hormonalaspectsofbc.com/p...211/index.html

Of note is that host says it can take 3 months before effectiveness is shown in hormonal therapy. Tumor can initially enlarge and Markers can rise even when eventually effective.


More on PET/CT as check:http://her2support.org/vbulletin/showthread.php?t=38950

[Nguyen]

I just find out that there are other patients who also respond to estradiol therapy after fulvestrant, so that aspect of it will need to be studied further.

Nguyen

[Rich66]

That's great. Always good to bypass conventional wisdom to our benefit

[Hopeful]

I think the researchers who designed the study wanted to allow time for the Fulvestrant to clear the body to avoid any confounders in their results. Good to know this may not be necessary.

Hopeful

[Nguyen]

Hi folks,

Thought I post an update to this since the tumours have started to grow again and we stop estradiol today and restart Femara. Wish us luck.

Nguyen

ps: I'd like to add a couple of details, today CT scan shows a couple of prior lung nodules either shrunk or disapppeared. It also shows (somewhat paradoxically) some prior nodules increase in size and multiple new nodules. The estradiol also greatly stimulate the growth (read increase chance of another cancer) of the uterus lining.

[Rich66]

How much mileage did you get out of the Estradiol?
Did Dr. Ellis contact you?

[Nguyen]

The estradiol gaves about 9-11 months of stabled disease. Yes I heard back from Dr. Ellis though just courteous email replied.

[Rich66]

Wow. That's good. Now I see you had a very detailed history at the top. Oops. Maybe you can bounce between estradiol and Femara.

Some have found Estrogen to work against advanced prostate cancer as well. My Dad's onc says it works but has been largely abandoned due to clotting risk. He used to get special pills for his patients from MD Amnderson. Did you come across that issue?

[Nguyen]

Well, the hope is her tumour would behave like below pattern, however I am not sure about given her estradiol again in the future, given the risk of it stimulating something else.

Nguyen

"In a subset of patients who were retreated with an AI after responding to estradiol, some responded and stabilized for a year or so. This included one patient who responded to 6 mg estradiol for 48 weeks, then progressed and resumed exemestane, which resulted in disease control for another 36 weeks. She progressed again and was retreated with estradiol for 12 weeks. She is now being treated with fulvestrant, Dr. Ellis said, calling this component of the study "a work in progress."

[Nguyen]

Update to this, we replace estradiol with Femara and it looks like the tumour is responding. Note that when I saw the CA27.29 rised to 65, I was thinking of abandoning the readdition of Femara and add Lapatinib. So hopefully this works for a few more months.

• 08/??/09: 80 CT shows growing nodules, double from 07/07 CT
• 09/14/09: 86 Keep Herceptin, STOPPED femara and fulvestrant
• 10/12/09: 85 Estradiol 12.32, start Estradiol
• 11/09/09: 88 Estradiol 512
• 12/07/09: 63
• 01/29/10: 53
• 03/01/10: 51
• 03/27/10: 55
• 04/26/10: 35
• 05/26/10: 45
• 06/18/10: 52
• 07/22/10: 53
• 08/09/10: CT scan shows new nodules, raplace estradiol with Femara
• 09/19/10: 65 MRI shows possible bone met (how long has it been there?)
• 10/07/10: 48 Bonescan shows no bone met, Zometa added (Onco believes MRI's result more)

[Rich66]

That's great. Thanks for the detailed updates.

[Nguyen]

After insurance refusal to pay for Pertuzumab and we couldn't get into T-DM1 trial, we are back to estradiol and it appears to be working again. Wish us luck that it'll work for a few months. Note that this was what Dr. Matthew Ellis discovered (estradiol also work the 2nd time around) several years ago. Also there was a poster at 2012 SABCS repeating the same estradiol experiments.

Linda's treatment history

12/2012 - current: 4mg estradiol, herceptin
08/2012 - 12/2012: Fulvestran 500mg, exemestane, Herceptin (Stop everolimus due to mouthsores)
05/2012 - 08/2012: Everolimus, Exemestane, Herceptin, Zometa
08/2011 - 05/2012: Herceptin, Tykerb, Femara, Zometa
08/2010 - 08/2011: Herceptin, Femara, Zometa
09-2009 - 08/2010: Herceptin and estradiol
09/2008 - 09/2009: Herceptin, Fulvestrant, Femara
03/2008 - 09/2008: Herceptin, Exemestane, Oophorectomy
01/2005 - 03/2008: Herceptin (readded) and Femara
07/2004: It returned again via several small nodules in the lung
10/2002: NED (via CT and CA27.29)!
10/2001 - 01/2005: Femara, (Fosamax)
12/2000 - 10/2001: Herceptin and Navelbine
12/2000: lung metastatic was diagnosed (a few small nodules)
02/1998 - 12/2000: Daily Tamoxifen
05/1997 - 04/1998: Modified Radical Mastectomy, many many cycles of chemo regiments (CAF,Taxol, Carpoplatin, Thiotepa, Navelbine, Taxotere), including HDC, and radiation
05/1997: First diagnosed with BC stage 3A, ER+, PR+, HER2 +, poorly differentiated, nuclear grade 3.

[Jackie07]

Thanks for the update. Sure is something good (Estradiol + Herceptin)to know.

Sending Linda good vibes.

[Laurel]

Wishing lots of luck! I hope this continues to work!