Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib.
OBJECTIVE
The value of the intrinsic subtypes of breast cancer (luminal A, luminal B, human epidermal growth factor receptor 2 [currently known as ERBB2, but referred to as HER2 in this study]-enriched, and basal-like) in the metastatic setting is currently unknown.


OBJECTIVE
To evaluate the association of the intrinsic subtypes of breast cancer with outcome and/or benefit in hormone receptor (HR)-positive metastatic breast cancer.


METHODS
Unplanned retrospective analysis of 821 tumor samples (85.7% primary and 14.3% metastatic) from the EGF30008 phase 3 clinical trial (NCT00073528), in which postmenopausal women with HR-positive invasive breast cancer and no prior therapy for advanced or metastatic disease were randomized to letrozole with or without lapatinib, an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Tumor samples were classified into each subtype using the research-based PAM50 classifier. Prior neoadjuvant/adjuvant antiestrogen therapy was allowed. Patients with extensive symptomatic visceral disease were excluded. Treatment effects were evaluated using interaction tests.


METHODS
Primary and secondary end points were progression-free survival and overall survival.


RESULTS
The median (range) age was 62 (31-94) years. Intrinsic subtype was the strongest prognostic factor independently associated with progression-free survival and overall survival in all patients, and in patients with HER2-negative (n = 644) or HER2-positive (n = 157) diseases. Median progression-free survival differed across the intrinsic subtypes of clinically HER2-negative disease: luminal A (16.9 [95% CI, 14.1-19.9] months), luminal B (11.0 [95% CI, 9.6-13.6] months), HER2-enriched (4.7 [95% CI, 2.7-10.8] months), and basal-like (4.1 [95% CI, 2.5-13.8] months). Median OS also differed across the intrinsic subtypes: luminal A (45 [95% CI, 41-not applicable {NA}] months), luminal B (37 [95% CI, 31-42] months), HER2-enriched (16 [95% CI, 10-NA] months), and basal-like (23 [95% CI, 12-NA] months). Patients with HER2-negative/HER2-enriched disease benefited from lapatinib therapy (median PFS, 6.49 vs 2.60 months; progression-free survival hazard ratio, 0.238 [95% CI, 0.066-0.863]; interaction P = .02).


CONCLUSIONS
This is the first study to reveal an association between intrinsic subtype and outcome in first-line HR-positive metastatic breast cancer. Patients with HR-positive/HER2-negative disease with a HER2-enriched profile may benefit from lapatinib in combination with endocrine therapy. The clinical value of intrinsic subtyping in hormone receptor-positive metastatic breast cancer warrants further investigation, but patients with luminal A/HER2-negative metastatic breast cancer might be good candidates for letrozole monotherapy in the first-line setting regardless of visceral disease and number of metastases.
Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain2Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain3Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Aleix
A
Prat
Division of Clinical Studies, Clinical Trials and Statistics Unit, Institute of Cancer Research, London, England.
Maggie C U
MC
Cheang
Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain3Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Patricia
P
Galván
Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Paolo
P
Nuciforo
Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain3Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Laia
L
Paré
Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain3Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Barbara
B
Adamo
Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain3Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Montserrat
M
Muñoz
Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain3Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Margarida
M
Viladot
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Michael F
MF
Press
Novartis, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Robert
R
Gagnon
GlaxoSmithKline Oncology, Collegeville, Pennsylvania.
Catherine
C
Ellis
Department of Medical Oncology, Royal Marsden Hospital, London, England.
Stephen
S
Johnston
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
D014408:Biomarkers, Tumor; D000077341:Lapatinib; D000077289:Letrozole; D009570:Nitriles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014230:Triazoles; C508053:ERBB2 protein, human