Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer.
BACKGROUND
Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study.


METHODS
DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM.


RESULTS
Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71-1.17)) or OS (HR 0.95 (0.71-1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37-0.85) for RAS MT and HR 0.69 (0.5-0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic.


CONCLUSIONS
Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.
1] Haematology-Oncology Department, The Queen Elizabeth Hospital, Woodville, SA 5011, Australia [2] School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
T J
TJ
Price
School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
M A
MA
Bruhn
NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
C K
CK
Lee
1] Haematology-Oncology Department, The Queen Elizabeth Hospital, Woodville, SA 5011, Australia [2] School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
J E
JE
Hardingham
1] Haematology-Oncology Department, The Queen Elizabeth Hospital, Woodville, SA 5011, Australia [2] School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
A R
AR
Townsend
NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
K P
KP
Mann
NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
J
J
Simes
1] Austin Health, Heidelberg, VIC 3084, Australia [2] Ludwig Institute for Cancer Research, Heidelberg, VIC 3084, Australia.
A
A
Weickhardt
Haematology-Oncology Department, The Queen Elizabeth Hospital, Woodville, SA 5011, Australia.
J W
JW
Wrin
NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
K
K
Wilson
NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
V
V
Gebski
Sir Charles Gardiner Hospital, Perth, WA, Australia.
G
G
Van Hazel
Christchurch Hospital, Christchurch, New Zealand.
B
B
Robinson
Royal Marsden Hospital, London, UK.
D
D
Cunningham
1] Austin Health, Heidelberg, VIC 3084, Australia [2] Ludwig Institute for Cancer Research, Heidelberg, VIC 3084, Australia.
N C
NC
Tebbutt
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D000069287:Capecitabine; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D011905:Genes, ras; D006801:Humans; D008297:Male; D016685:Mitomycin / Q000008:administration & dosage; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis
D061067:Antibodies, Monoclonal, Humanized; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D000068258:Bevacizumab; D016685:Mitomycin; D000069287:Capecitabine; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D005472:Fluorouracil