Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact.
BACKGROUND
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC.


METHODS
Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks, followed by four cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody.


RESULTS
Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% [95% CI: 41.1% to 69.5%] according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR.


CONCLUSIONS
Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC.


BACKGROUND
NCT00933517.
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Clinical and Translational Research Division, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand CIC 501, UMR 766, Clermont-Ferrand jmnabholtz@cjp.fr.
J M
JM
Nabholtz
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Clinical and Translational Research Division, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand CIC 501, UMR 766, Clermont-Ferrand.
C
C
Abrial
ERTICA EA 4677, University of Auvergne, Clermont-FerrandDepartments of Medical Oncology, Clermont-Ferrand.
M A
MA
Mouret-Reynier
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Biopathology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand.
M M
MM
Dauplat
Alexis Vautrin Comprehensive Cancer Centre, Nancy.
B
B
Weber
Tenon University Hospital, Paris.
J
J
Gligorov
Montluçon Hospital Centre, Montluçon.
A M
AM
Forest
Leon Berard Comprehensive Cancer Centre, Lyon.
O
O
Tredan
Oscar Lambret Comprehensive Cancer Centre, Lille.
L
L
Vanlemmens
Paul Strauss Comprehensive Cancer Centre, Strasbourg.
T
T
Petit
Georges François Leclerc Comprehensive Cancer Centre, Dijon.
S
S
Guiu
Departments of Medical Oncology, Clermont-Ferrand.
I
I
Van Praagh
Jean Godinot Comprehensive Cancer Institute, Reims.
C
C
Jouannaud
ERTICA EA 4677, University of Auvergne, Clermont-FerrandDepartments of Medical Oncology, Clermont-Ferrand.
P
P
Dubray-Longeras
Limoges University Hospital, Limoges.
N
N
Tubiana-Mathieu
Departments of Medical Oncology, Clermont-Ferrand.
K E
KE
Benmammar
Departments of Medical Oncology, Clermont-Ferrand.
S
S
Kullab
Departments of Medical Oncology, Clermont-Ferrand Oncauvergne Regional Oncology Network.
M R K
MR
Bahadoor
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Biopathology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand.
N
N
Radosevic-Robin
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Clinical and Translational Research Division, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand LMB GenAuvergne Oncogenetics Department, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand.
F
F
Kwiatkowski
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand LMB GenAuvergne Oncogenetics Department, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand.
A
A
Desrichard
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand CIC 501, UMR 766, Clermont-Ferrand.
A
A
Cayre
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand LMB GenAuvergne Oncogenetics Department, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand.
N
N
Uhrhammer
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Clinical and Translational Research Division, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand CIC 501, UMR 766, Clermont-Ferrand.
N
N
Chalabi
Clinical and Translational Research Division, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand Inserm UMR 990, Clermont-Ferrand University of Auvergne, Clermont-Ferrand, France.
P
P
Chollet
ERTICA EA 4677, University of Auvergne, Clermont-Ferrand Biopathology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand.
F
F
Penault-Llorca
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000077544:Panitumumab; D010865:Pilot Projects; D011379:Prognosis; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery
D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D000077544:Panitumumab
anti-EGFR therapy; neoadjuvant chemotherapy; panitumumab; pathological complete response; predictive biomarkers; triple-negative breast cancer