The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers

• Published in: Breast cancer research and treatment 2007-03, Vol.102 (1), p.43-49
• Main Authors: MARCOM, P. Kelly, ISAACS, Claudine, HARRIS, Lyndsay, ZEE WANG WONG, KOMMARREDDY, Aruna, NOVIELLI, Nellie, MANN, Gretchen, YU TAO, ELLIS, Matthew J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Aromatase; Biochemistry; Biological and medical sciences; Breast cancer; Breast Neoplasms - chemistry; Breast Neoplasms - drug therapy; Cancer research; Cancer therapies; Clinical trials; Endocrine therapy; ErbB-2 protein; Estrogen receptors; Estrogens; Female; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Mammary gland diseases; Medical sciences; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Oncology; Patients; Pharmacology; Progesterone; Receptor, ErbB-2 - analysis; Receptors, Estrogen - analysis; Toxicity; Trastuzumab; Triazoles - administration & dosage; Triazoles - adverse effects; Tumors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-006-9307-8

Estrogen receptor (ER) and/or progesterone receptor expression occurs in approximately 50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study. Patients with ER+ and/or PgR+ and HER2+ (IHC 2+ or 3+ or FISH+) advanced breast cancer were treated with trastuzumab plus letrozole until disease progression or unacceptable toxicity. Thirty-three patients were enrolled, of which thirty one were considered evaluable. The majority of patients (82%) had received tamoxifen and 82% had HER2 FISH+ and/or IHC 3+ tumors. Eight patients responded (1 CR and 7 PR) for an overall response rate (ORR) of 26% and a clinical benefit rate (CBR) of 52%. The median time to progression (TTP) was 5.8 months and the median duration of response (DOR) was 20.6+ months. Excluding IHC 2+, FISH- tumors, the OR was 24%, CBR 44%, TTP 5.5 months and DOR 17+ months. The combination was well tolerated with only two toxicity events requiring termination of study medication. Combined trastuzumab and letrozole treatment for patients with HER2+ and ER+ advanced breast cancer produced durable responses consistently lasting at least 1 year in one quarter of the patients. While these data are promising for a subgroup, for half the patients, trastuzumab plus letrozole was inactive. This finding demonstrates ER+ HER2+ advanced disease is heterogeneous and additional agents will be required for optimal management based on targeted therapeutics alone.