Summary Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic ...colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre- KRAS selection era. Methods 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS , and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings 40·0% (299/747) of the tumours harboured a KRAS mutation, 14·5% (108/743) harboured a PIK3CA mutation (of which 68·5% 74/108 were located in exon 9 and 20·4% 22/108 in exon 20), 4·7% (36/761) harboured a BRAF mutation, and 2·6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7% (17/253) versus 35·8% (126/352; odds ratio OR 0·13, 95% CI 0·07–0·22; p<0·0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio HR 1·98, 1·66–2·36; p<0·0001), and a median overall survival of 32 weeks versus 50 weeks (1·75, 1·47–2·09; p<0·0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8·3% (2/24) in carriers of BRAF mutations versus 38·0% in BRAF wild types (124/326; OR 0·15, 95% CI 0·02–0·51; p=0·0012); and 7·7% (1/13) in carriers of NRAS mutations versus 38·1% in NRAS wild types (110/289; OR 0·14, 0·007–0·70; p=0·013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0·0% (0/9) versus 36·8% (121/329; OR 0·00, 0·00–0·89; p=0·029), a median PFS of 11·5 weeks versus 24 weeks (HR 2·52, 1·33–4·78; p=0·013), and a median overall survival of 34 weeks versus 51 weeks (3·29, 1·60–6·74; p=0·0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS , and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24·4% in the unselected population, 36·3% in the KRAS wild-type selected population, and 41·2% in the KRAS, BRAF, NRAS , and PIK3CA exon 20 wild-type population. Interpretation While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS , and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS , and PIK3CA exon 20 mutations in a KRAS wild-type population. Funding Belgian Federation against Cancer (Stichting tegen Kanker).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Preliminary evidence suggests that magnesium wasting occurs in patients who are treated with epidermal-growth-factor receptor (EGFR)-targeting antibodies for colorectal cancer. The ...mechanism of this side-effect is unknown, and if all or a subset of patients are affected is also unclear. We aimed to assess the incidence, characteristics, and predictive factors of magnesium wasting during treatment with EGFR-targeting antibodies, and to study the pathophysiology of this phenomenon. Methods We measured prospectively magnesium concentrations in a cohort of 98 patients with colorectal cancer treated with EGFR-targeting antibodies with or without combined chemotherapy. The primary outcome measure was the slope of the serum magnesium concentrations over time. In 35 patients, 24-h urinary magnesium excretion was measured. In a subset of patients (n=5), an intravenous magnesium load test was done. 16 patients who had chemotherapy alone acted as controls. A clinical protocol was written before initiation of the study, but because this was a non-interventional study, the protocol was not formally registered. Findings 95 (97%) patients had decreasing serum magnesium concentrations during EGFR-targeting treatment compared with baseline measurements. The mean serum magnesium slope during EGFR-targeting treatment (with or without combined chemotherapy) was significantly lower compared with chemotherapy alone (−0·00157 mmol/L/day, SD 0·00162 95% CI −0·00191 to −0·00123 vs 0·00014 mmol/L/day, SD −00076 −0·00026 to 0·00055; ( t test, p < 0·0001). 24-h urine analysis and intravenous magnesium load tests showed a defect in renal magnesium reabsorption. Interpretation EGFR-inhibiting antibodies compromised the renal magnesium retention capacity, leading to hypomagnesaemia in most patients. Future studies should address the effects of exposure and target affinity. Our study suggests a pivotal role of the EGFR-signalling pathway in regulating magnesium homoeostasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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