Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039).
OBJECTIVE
Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.


METHODS
Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2(+) was defined as 2+/3+ by IHC and FISH(+).


RESULTS
One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2(+), 78% were HER2(-) nonamplified, 26% were EGFR(+). Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (-31%; P < 0.001), but not with placebo (-3%). Whereas Ki67 reduction with lapatinib was greatest in HER2(+) breast cancer (-46%; P = 0.003), there was a significant Ki67 decrease in HER2(-) breast cancer (-27%; P = 0.017) with 14% of HER2(-) breast cancer demonstrating ≥50% Ki67 reduction with lapatinib. Among HER2(+) patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho = -0.7; P = 0.002). Among HER2(-) tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P = 0.01). In HER2(-) breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression.


CONCLUSIONS
Lapatinib has antiproliferative effects in a subgroup of HER2(-) nonamplified tumors characterized by high HER3 expression. The possible role of high HER2:HER3 heterodimers in predicting response to lapatinib merits investigation in HER2(-) tumors.
Institut de Cancerologie, Gustave Roussy, Villejuif, France.
Alexandra
A
Leary
Poole Hospital NHS Foundation Trust, Poole, United Kingdom.
Abigail
A
Evans
The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom. Stephen.johnston@rmh.nhs.uk.
Stephen R D
SR
Johnston
The Institute of Cancer Research-Clinical Trials and Statistics Unit, Division of Clinical Studies, Sutton, United Kingdom.
Roger
R
A'Hern
The Institute of Cancer Research-Clinical Trials and Statistics Unit, Division of Clinical Studies, Sutton, United Kingdom.
Judith M
JM
Bliss
DNA Electronics Ltd., London, United Kingdom.
Rashmita
R
Sahoo
Academic Department of Biochemistry, Royal Marsden NHS Foundation Trust, London, United Kingdom.
Simone
S
Detre
The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
Benjamin P
BP
Haynes
Academic Department of Biochemistry, Royal Marsden NHS Foundation Trust, London, United Kingdom.
Margaret
M
Hills
Maidstone and Tunbridge Wells NHS Foundation Trust, Kent, United Kingdom.
Catherine
C
Harper-Wynne
University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
Nigel
N
Bundred
The Institute of Cancer Research-Clinical Trials and Statistics Unit, Division of Clinical Studies, Sutton, United Kingdom.
Gill
G
Coombes
The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
Ian
I
Smith
The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom. Academic Department of Biochemistry, Royal Marsden NHS Foundation Trust, London, United Kingdom.
Mitch
M
Dowsett
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D057234:Preoperative Period; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human