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Nguyen · 05-06-2010, 12:34 PM

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)...."

05-06-2010, 12:34 PM	#1
Nguyen Senior Member Join Date: Nov 2005 Posts: 523	Counterintuitive, estradiol as treatment 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)...."