Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study.
OBJECTIVE
We report a retrospective exploratory analysis of the association of the research-based prediction analysis of microarray 50 (PAM50) subtype predictor with pathologic complete response (pCR) and event-free survival (EFS) in women enrolled in the NeOAdjuvant Herceptin (NOAH) trial.


METHODS
Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded core biopsies from 114 pretreated patients with HER2-positive (HER2(+)) tumors randomized to receive neoadjuvant doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF), or the same regimen in combination with trastuzumab for one year. A control cohort of 42 patients with HER2-negative tumors treated with AT-CMF was also included. The PAM50 subtypes, the PAM50 proliferation score, and the PAM50 risk of relapse score based on subtype (RORS) and subtype and proliferation (RORP) were evaluated.


RESULTS
HER2-enriched (HER2-E) tumors predominated within HER2(+) disease, although all PAM50 intrinsic subtypes were identified across the three cohorts. The OR for achieving pCR with trastuzumab-based chemotherapy for HER2(+)/HER2-E and HER2(+)/RORP-high were 5.117 (P = 0.009) and 8.469 (P = 0.025), respectively, compared with chemotherapy only. The pCR rates of HER2(+)/HER2-E and HER2(+)/RORP-high after trastuzumab-based chemotherapy were 52.9% and 75.0%, respectively. A statistically nonsignificant trend was observed for more pronounced survival benefit with trastuzumab in patients with HER2(+)/HER2-E and HER2(+)/RORP-high tumors compared with patients with HER2(+)/non-HER2-E and HER2(+)/non-RORP-high tumors, respectively.


CONCLUSIONS
As determined by EFS and pCR, patients with HER2(+)/HER2-E tumors, or HER2(+)/RORP-high tumors, benefit substantially from trastuzumab-based chemotherapy. The clinical value of this genomic test within HER2(+) disease warrants further investigation.
Authors' Affiliations: Translational Genomics Group, Vall d'Hebron Institute of Oncology; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona; Hospital Clinico Universitario, Valencia, Spain; Oncologia Medica, San Raffaele Cancer Centre, Milan, Italy; Roche, Pharma Research and Early Development, Penzberg; Frauenklinik vom Roten Kreuz, Munich, Germany; University of North Carolina, Chapel Hill, North Carolina; NN Petrov Research Institute of Oncology, St Petersburg, Russian Federation; NN Blokhin Russian Cancer Centre; Central Clinical Hospital named after N A Semashko, Moscow, Russia; and Memorial Sloan-Kettering Cancer Center, New York, New York.
Aleix
A
Prat
Giampaolo
G
Bianchini
Marlene
M
Thomas
Anton
A
Belousov
Maggie C U
MC
Cheang
Astrid
A
Koehler
Patricia
P
Gómez
Vladimir
V
Semiglazov
Wolfgang
W
Eiermann
Sergei
S
Tjulandin
Mikhail
M
Byakhow
Begoña
B
Bermejo
Milvia
M
Zambetti
Federico
F
Vazquez
Luca
L
Gianni
José
J
Baselga
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D000068878:Trastuzumab; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab