Ciência e terapia do câncer

Letrozole and Fulvestrant Combination in Second Line or More for Estrogen Receptor Positive Metastatic Breast Cancer; Efficacy and Predictive Factors of Response

Abstract

M.S. Copur, A.M. Obermiller R, Ramaekers, M. Bolton, B. Luebbe, S. Schneider, J. Goering, W. Marsh, D. Novinski, K. Mleczko, S. Woodward, B. Keenportz, S. Frankforter and Max Norvell

Background: Preclinical data show that complete estrogen blockade by both down regulating estrogen receptor and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone. Combination of an aromatase inhibitor and fulvestrant may be an optimal second line therapy by preventing activation of growth factor pathways and possible cross talk with ER. One clinical study has shown no benefit of adding anastrozole to fulvestrant at first relapse. No clinical data on combination letrozole and fulvestrant in the second line or more metastatic beast cancer setting is available.

Methods: Estrogen receptor (ER) positive, progesterone receptor (PgR) positive or negative metastatic breast cancer patients with prior chemo and/or non-aromatase inhibitor (non-AI) endocrine therapy were treated with letrozole and fulvestrant. Patients with complete response(CR) partial response(PR), or stable disease(SD) were considered to have clinical benefit (CR+PR+SD). The predictive effects of age, number of prior regimens, ER/PgR status, histology, sites of metastatic disease were examined using Chi-square test.

Results: Thirty-two patients received oral letrozole 2.5 mg daily plus fulvestrant 250 mg intramuscular injection monthly. Mean age was 70 (range: 35-92), median number of prior treatments was 2 (range2-6). 25 pts had ER+/ PgR+, 7 pts had ER+/PgR- tumors. Twenty-five patients had prior non-AI endocrine therapy. Eight patients had lobular histology. Overall clinical benefit rate was 71% (3 CR, 7 PR, and 13 SD). Mean duration of the clinical benefit was 15 months (range 2-38). Nine patients progressed under therapy. Age more than 65 versus younger (89% vs 46%, P=0.007), prior treatments less than 4 versus more (87% vs 25%, P=0.0007) and ER+/PgR+ versus ER+/PgR- (84% versus 42%, P<0.05) were predictive of clinical benefit; lobular histology, bone versus visceral metastases and prior endocrine therapy did not have affect clinical benefit rate (P>0.05) .

Conclusions: In previously treated metastatic breast cancer patients, combination of letrozole and fulvestrant can be effective with a mean clinical benefit duration of 15 months. Older age, less than four prior lines of therapy, and expression of both ER/PgR are predictive of clinical benefit while lobular histology, site of metastatic disease and prior non-AI endocrine therapy are not. Letrozole and fulvestrant combination can be a reasonable option in selected group of previously treated metastatic breast cancer patients and should be further evaluated in larger studies utilizing recently approved high dose (500 mg) fulvestrant schedule.