title: Dose-dependent change in biomarkers during neoadjuvant  endocrine therapy with fulvestrant: results from NEWEST,  a randomized Phase II study.
abstract: NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.
authors.affiliation: Massachusetts General Hospital, Professional Office Building 228, 55 Fruit Street, Boston, MA 02114, USA. ikuter@partners.org
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.forename: Roberto
authors.initials: R
authors.lastname: Hegg
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Rajendra A
authors.initials: RA
authors.lastname: Badwe
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Lowe
authors.forename: Ugochi A
authors.initials: UA
authors.lastname: Emeribe
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.forename: Francisco
authors.initials: F
authors.lastname: Sapunar
authors.forename: Pauline
authors.initials: P
authors.lastname: Finlay
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: José
authors.initials: J
authors.lastname: Bines
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D004958:Estradiol