low dose estradiol for AI resistance

[Nguyen]

A revalidation of Dr. Matthew Ellis low dose estradiol work. This time with only 2mg.

Nguyen

SABCS 2012: P2-14-06

A phase II trial of low dose estradiol in postmenopausal women
with advanced breast cancer and acquired resistance to an
aromatase inhibitor.
Howell SJ, Seif MW, Armstrong AC, Cope J, Wilson G, Welch RS,
Misra V, Ryder D, Blowers E, Palmieri C, Wardley AM. University of
Manchester, United Kingdom; The Christie NHS Foundation Trust,
Manchester, United Kingdom; Imperial College, London, United
Kingdom
Background High dose estrogen (HDE) is an effective but toxic
treatment for postmenopausal women with advanced breast
cancer (ABC). In vitro, prolonged periods of estrogen deprivation
(ED) sensitises cancers to the inhibitory effects of estrogen. We
hypothesised that the profound ED seen with third generation
aromatase inhibitor (AI) would sensitise cancers to LDE which would
be better tolerated.
Methods Single arm phase II study in postmenopausal women
with measurable ER+ ABC and demonstrated clinical benefit (CB)
with a third generation AI. Treatment: estradiol valerate 2mg daily.
Primary endpoint: CB rate (CBR) was correlated with baseline and
dynamic LH/FSH levels and on-treatment estradiol levels. Secondary
endpoints included TTF, PFS, toxicity and QoL. If LDE was effective,
retreatment with the AI on which the cancer had progressed prior
to study entry was offered on progression. If LDE was ineffective
HDE was offered.
Results 21/50 patients were recruited before early closure due to slow
accrual. 19 were assessable for efficacy and toxicity (1 ineligible; 1
no LDE). CBR was 5/19 (26%; 95%CI 9.1%,51.2%). Median TTF
2.8months (range 0.5-29.8). CBR durations were 11.1, 16.8, 17.3*,
19.8, 29.8 months (*censored). 4 stopped treatment early due to
toxicity (G4 hypercalcaemia/ G2 vaginal bleeding (VB) plus G4
hyponatraemia/ G2 mucositis/ G2 headaches) 1 with SD at 3 months
and 3 before response assessment. Other common toxicities were all
G1/2 and mainly limitted to nausea (8/19), breast pain (7/19) and
tumour flare (7/19). VB occurred in 8/11 without prior hysterectomy.
Baseline LH correlated with CBR by logistic regression (p=0.01). Of
3 retreated with the same AI post LDE; 1 had PR, 1 SD ≥6months
and 1 PD. One woman received HDE after failure of LDE and
achieved a PR.
Conclusion LDE is an effective and largely well tolerated treatment
in women with acquired resistance to AI. VB is common without
prior hysterectomy. Rechallenge with the same AI post LDE seems
effective and may offer an extra line of endocrine therapy. This should
be tested in future trials.