PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients.
OBJECTIVE
EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.


METHODS
This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.


RESULTS
Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).


CONCLUSIONS
Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.
Institut Curie, Paris, France.
Anne
A
de la Rochefordiere
Institut Curie, Paris, France.
Maud
M
Kamal
Institut Bergonnié, Bordeaux, France.
Anne
A
Floquet
Institut Bergonnié, Bordeaux, France.
Laurence
L
Thomas
Institut Curie, Paris, France.
Peter
P
Petrow
Centre Paul Strauss, Strasbourg, France.
Thierry
T
Petit
Centre Paul Strauss, Strasbourg, France.
Marius
M
Pop
Centre Val d'Aurelle - Paul Lamarque, Montpellier, France.
Michel
M
Fabbro
Centre Val d'Aurelle - Paul Lamarque, Montpellier, France.
Christine
C
Kerr
Centre Regional Francois Baclesse, Caen, France.
Florence
F
Joly
Centre Regional Francois Baclesse, Caen, France.
Emmanuel
E
Sevin
Institut Jean Godinot, Reims, France.
Sophie
S
Maillard
Institut Jean Godinot, Reims, France.
Hervé
H
Curé
Centre Alexis Vautrin, Nancy, France.
Béatrice
B
Weber
Centre Alexis Vautrin, Nancy, France.
Claire
C
Brunaud
Institut Paoli Calmettes, Marseille, France.
Mathieu
M
Minsat
Institut Paoli Calmettes, Marseille, France.
Laurence
L
Gonzague
Institut de cancérologie de l'Ouest, René Gauducheau, France.
Dominique
D
Berton-Rigaud
Institut de cancérologie de l'Ouest, René Gauducheau, France.
Maud
M
Aumont
Institut Claudius Régaud, Toulouse, France.
Laurence
L
Gladieff
Centre Georges-François Leclerc, Dijon.
Karine
K
Peignaux
Institut Curie, Paris, France.
Virginie
V
Bernard
Institut Curie, Paris, France.
Quentin
Q
Leroy
Institut Curie, Paris, France.
Ivan
I
Bieche
Institut Curie, Paris, France.
Audrey
A
Margogne
Institut Curie, Paris, France.
AnaTereza
A
Nadan
Institut Curie, Paris, France.
Virginie
V
Fourchotte
Institut Curie, Paris, France.
Alhassane
A
Diallo
Institut Curie, Paris, France.
Benard
B
Asselain
Institut Curie, Paris, France.
Corine
C
Plancher
Institut Curie, Paris, France.
Sébastien
S
Armanet
Institut Curie, Paris, France.
Philippe
P
Beuzeboc
Institut Curie, Paris, France. suzy.scholl@curie.fr.
Suzy M
SM
Scholl
D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D000068818:Cetuximab / Q000008:administration & dosage*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D018631:ras Proteins / Q000235:genetics
D000091162:AMP-Activated Protein Kinase Kinases; D000068818:Cetuximab; D002945:Cisplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C109790:STK11 protein, human