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PIK3CA mutation in metastatic colorectal cancer (mCRC): Association with clinico-pathological features and outcome
abstracts 1 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China, 2Colorectal Cancer Center; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China,
630P
mCRC gene profiling using the Idylla platform
C. Bricogne1, M. Rodriguez-Justo2, A. Agarwal3, S. Khan2, D. Patel2, N. Bhuva4, S. Brown4, R. Wikinson4, K-K. Shiu1 1 Oncology Department, University College London Hospital, London, UK, 2Pathology Department, University College London Hospital, London, UK, 3Pathology Department, Mount Vernon Hospital, London, UK, 4Oncology Department, Mount Vernon Hospital, London, UK Background: KRAS, NRAS and BRAF mutation testing for metastatic colorectal cancer (mCRC) is essential to guide treatment and prognostication. Multiple gene profiling assays are available, each with differing tumour sample size/quality requirements and turnaround time (TAT). Many UK hospitals send samples to off-site labs for profiling. A rapid TAT is desirable to plan appropriate chemotherapy þ/- biologics from cycle one, as well as providing certainty and satisfaction for patients and clinicians. Methods: This study was conducted at 2 UK tertiary cancer centres (University College London Hospital and Mount Vernon Hospital), comparing a pathway where gene profiling of mCRC was performed off-site using an NGS platform versus on-site testing using the Idylla platform (Biocartis, Mechelen, Belgium). Up to 50 patients were included in each group with 8 of the Idylla tests being used for samples that had failed with the NGS platform. Results: Mutational profiling results for the whole cohort that were successfully tested (n ¼ 84) showed 26% (22/84) were wildtype for KRAS/NRAS/BRAF, 62% (52/84) KRAS mutated, 2% (2/84) NRAS mutated, 10% (8/84) BRAF mutated. The median TAT in days (median, interquartile range (IQR)) of the on-site Idylla pathway was shorter than the off-site NGS pathway (4, 1 - 6 vs. 15, 13-17; p ¼ <0.0001). In the offsite group median time from request to receipt of sample was 3 days (IQR 2 - 5) and median time from receipt to result was 10 days (IQR 9 - 13). Test failure rate was significantly higher with the NGS test (30%, 15/50) compared to the Idylla test (2%, 1/50) (p ¼ 0.0001). 8 samples that had failed testing with the NGS platform, due to insufficient/low quality of sample, were all successfully tested with the Idylla platform. Conclusions: For gene profiling of mCRC, on-site testing with the Idylla platform significantly shortened the TAT, lowered failure rate and was able to test more sub-optimal samples compared to off-site NGS testing. Updated results integrating these data with tumour location, MMR status and treatment outcomes will be presented at ESMO 2019. Legal entity responsible for the study: The authors. Funding: Biocartis provided the Idylla test kits for this study without charge. Disclosure: N. Bhuva: Honoraria (self), supported in attending international meetings: Amgen; Honoraria (self), supported in attending international meetings: Bristol-Myers Squibb. K. Shiu:
v238 | Gastrointestinal Tumours, Colorectal
Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Roche; Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Merck Group; Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Servier; Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Guardant Health. All other authors have declared no conflicts of interest.
631P
PIK3CA mutation in metastatic colorectal cancer (mCRC): Association with clinico-pathological features and outcome
V. Fanotto1, G. Zucchelli2, M.M. Germani2, D. Rossini2, E. Sensi3, C. Lupi3, C. Ugolini3, C. Antoniotti2, F. Marmorino2, R. Moretto2, A. Boccaccino2, B. Borelli2, V. Conca2, E. Ongaro4, G. Masi2, G. Fontanini5, A. Falcone2, C. Cremolini2 1 Department of Medicine (DAME), University of Udine, Udine, Italy, 2Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy, 3Unit of Pathology 3, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, 4SOC Oncologia Medica e Prevenzione Oncologica, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano, Italy, 5Department of Surgical, Medical, Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy Background: Mutations in PIK3CA, an EGFR downstream effector, and the subsequent activation of AKT pathway plays an important role in colorectal carcinogenesis. Considering the frequent co-occurrence of PIK3CA and RAS mutations, conflicting data exist about its impact on prognosis of mCRC patients (pts) and its predictive role to anti-EGFR therapy. However, PI3K inhibitors have been developed and are currently under investigation in mCRC. Methods: Data from mCRC pts treated at Azienda Ospedaliero-Universitaria Pisana from 1 Jan 2005 to 31 Dec 2017, whose tumours had been analysed per clinical practice by MALDI-TOF MassArray were retrieved. Association between PIK3CA mutation and clinico-pathological features was analysed by v2 test; OS curves were estimated with Kaplan-Meier method and compared by log-rank test. Results: Tumours from 90 (17%) out of 542 pts included in this analysis were PIK3CA mutated (mut), most of them in exon 9 (58.9%) or 20 (21.1%). Compared to PIK3CA wild-type (wt) tumours, mut ones were more often RAS mut (P ¼ 0.006), MSI high (P ¼ 0.008), and right-sided (P ¼ 0.0004). Among 53 pts for whom PIK3CA status was available on both primary tumours (PT) and metastasis, the concordance was 92.4%. PIK3CA mutations were not associated with OS (36.4 vs 35.9 mos, HR 1.17, 95%CI 0.85-1.62, p ¼ 0.3), with no difference among those affecting exon 9 and 20 (36.4 vs 27.5 mos, HR 0.77, 95%CI 0.39-1.54, p ¼ 0.44). In RAS/BRAF wt (N 188) and in RAS mut (N 299) subgroup, no difference in terms of OS was found between PIK3CA mut and wt pts (38.1 vs 44.4 mos, HR 1.22, 95%CI 0.60-2.48, p ¼ 0.55 and 27.5 vs 34.4 mos, HR 1.26, 95%CI 0.85-1.86, p ¼ 0.22, respectively), though PIK3CA mut had shorter OS. In BRAF mut subgroup (N 54), PIK3CA mut pts had longer OS compared to PIK3CA wt (not reached vs 14.4 mos, HR 0.37, 95%CI 0.16-0.85, p ¼ 0.09). Among 39 chemorefractory RAS/BRAF wt pts evaluable for response to an anti-EGFR agent, only 2 were exon 9 PIK3CA mut and achieved stable disease. Conclusions: PIK3CA mut tumours displayed specific clinico-pathological features and a strong concordance was found between PT and paired metastases. Interestingly, a different impact on prognosis of PIK3CA mutation in RAS/BRAF wt, RAS mut or BRAF mut mCRC pts was observed and deserves validation. Legal entity responsible for the study: The authors. Funding: Supported by ARCO (Associazione Ricerca e Cure in Oncologia) Foundation. Disclosure: All authors have declared no conflicts of interest.
632P
Patient-derived xenografts (PDX) identify JMJD6 inhibitor as an effective therapeutic medicine in colorectal cancer
F. Ye1, J. You2, L. Xia3, J. Lian3, R. Xiao4, T. Ran4, X. Gao4, J. Li1, X. Zhao1, J. Gao2, H. Lin2, J. Zheng1, W. Liu4 1 Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China, 2Department of Gastrointestinal Surgery, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China, 3Laboratory of Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China, 4 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, China Background: The Jmjc-domain-containing protein 6 (JMJD6) is a member of JmjC oxygenases that contain both arginine demethylase and lysine hydroxylase activities. Overexpression of JMJD6 has been reported to be associated with the development of various types of cancers, such as breast, lung, liver, and colon cancer. The present study aimed to explore the inhibitory effect of the small-molecule JMJD6 inhibitor named WL8 obtained by virtual screening on the progression of colorectal cancer. Methods: WL8 was administered to a mouse bearing xenografts of human colorectal cancer tissue, once every 7 days for 3 times. We analyzed the response of tumors from three patients to the JMJD6 inhibitor (11.5mg/kg, intrapertoneally, i.p.), and to FOLFOX (oxaliplatin 12mg/kg, calcium levifolinate 30mg/kg, 5-fluorouracil 55mg/kg, i.p.) or FOLFIRI (irinotecan 40mg/kg, calcium levifolinate 30mg/kg, 5-fluorouracil 55mg/kg, i.p.), as well as to combined usage of JMJD6 inhibitor and FOLFOX or FOLFIRI in PDX models by recording the tumors sizes every 3 or 4 days for 7 times.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz246.108/5577909 by guest on 27 October 2019
Background: Drug resistance is an important clinical problem affecting the prognosis of colorectal cancer patients with initially unresectable liver metastases. The role of 5hydroxymethylcytosine (5-hmC) in this process is still unknown. Methods: A single-center study was conducted to enroll colorectal cancer patients with initially unresectable liver metastases at Zhongshan Hospital, Shanghai. The 5-hmC levels of each gene locus in circulating-free DNA (cfDNA) were detected using a highly sensitive sequencing method before the patient received any conversion therapy. Eight weeks after conversion therapy, patients with disease progression according to RECIST 1.1 were defined as drug-resistant group, while patients with complete response, partial response and stable disease were defined as the drug-effective group. By using the gene loci with the most significant difference of 5-hmC level, a predictive model (Logistic regression) was established based on machine-learning method. Then, we validated the model. Results: From June 2018 to January 2019, 35 patients were enrolled, including 20 patients in drug-effective group and 15 in drug-resistant group. The predictive model was established using the first 100 significantly different gene loci and 10 loci were included in the model. The internal validation results suggested that the sensitivity (predictive accuracy for drug-resistant patients) and specificity (predictive accuracy for drug-effective patients) were 86.7% and 95.0%, respectively, and the area under the ROC curve is 0.990. Conclusions: Our study screened the gene loci with different 5-hmC level between drug-effective and drug-resistant colorectal cancer patients with initial unresectable liver metastases. Then we established a predictive model for the efficacy of conversion therapy, although this model is still being improved and validated by enrolling more subjects. Clinical trial identification: NCT03679039 09/18/2018. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
630P
mCRC gene profiling using the Idylla platform
C. Bricogne1, M. Rodriguez-Justo2, A. Agarwal3, S. Khan2, D. Patel2, N. Bhuva4, S. Brown4, R. Wikinson4, K-K. Shiu1 1 Oncology Department, University College London Hospital, London, UK, 2Pathology Department, University College London Hospital, London, UK, 3Pathology Department, Mount Vernon Hospital, London, UK, 4Oncology Department, Mount Vernon Hospital, London, UK Background: KRAS, NRAS and BRAF mutation testing for metastatic colorectal cancer (mCRC) is essential to guide treatment and prognostication. Multiple gene profiling assays are available, each with differing tumour sample size/quality requirements and turnaround time (TAT). Many UK hospitals send samples to off-site labs for profiling. A rapid TAT is desirable to plan appropriate chemotherapy þ/- biologics from cycle one, as well as providing certainty and satisfaction for patients and clinicians. Methods: This study was conducted at 2 UK tertiary cancer centres (University College London Hospital and Mount Vernon Hospital), comparing a pathway where gene profiling of mCRC was performed off-site using an NGS platform versus on-site testing using the Idylla platform (Biocartis, Mechelen, Belgium). Up to 50 patients were included in each group with 8 of the Idylla tests being used for samples that had failed with the NGS platform. Results: Mutational profiling results for the whole cohort that were successfully tested (n ¼ 84) showed 26% (22/84) were wildtype for KRAS/NRAS/BRAF, 62% (52/84) KRAS mutated, 2% (2/84) NRAS mutated, 10% (8/84) BRAF mutated. The median TAT in days (median, interquartile range (IQR)) of the on-site Idylla pathway was shorter than the off-site NGS pathway (4, 1 - 6 vs. 15, 13-17; p ¼ <0.0001). In the offsite group median time from request to receipt of sample was 3 days (IQR 2 - 5) and median time from receipt to result was 10 days (IQR 9 - 13). Test failure rate was significantly higher with the NGS test (30%, 15/50) compared to the Idylla test (2%, 1/50) (p ¼ 0.0001). 8 samples that had failed testing with the NGS platform, due to insufficient/low quality of sample, were all successfully tested with the Idylla platform. Conclusions: For gene profiling of mCRC, on-site testing with the Idylla platform significantly shortened the TAT, lowered failure rate and was able to test more sub-optimal samples compared to off-site NGS testing. Updated results integrating these data with tumour location, MMR status and treatment outcomes will be presented at ESMO 2019. Legal entity responsible for the study: The authors. Funding: Biocartis provided the Idylla test kits for this study without charge. Disclosure: N. Bhuva: Honoraria (self), supported in attending international meetings: Amgen; Honoraria (self), supported in attending international meetings: Bristol-Myers Squibb. K. Shiu:
v238 | Gastrointestinal Tumours, Colorectal
Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Roche; Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Merck Group; Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Servier; Honoraria (self), Advisory / Consultancy, supported in attending lectures and conferences: Guardant Health. All other authors have declared no conflicts of interest.
631P
PIK3CA mutation in metastatic colorectal cancer (mCRC): Association with clinico-pathological features and outcome
V. Fanotto1, G. Zucchelli2, M.M. Germani2, D. Rossini2, E. Sensi3, C. Lupi3, C. Ugolini3, C. Antoniotti2, F. Marmorino2, R. Moretto2, A. Boccaccino2, B. Borelli2, V. Conca2, E. Ongaro4, G. Masi2, G. Fontanini5, A. Falcone2, C. Cremolini2 1 Department of Medicine (DAME), University of Udine, Udine, Italy, 2Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy, 3Unit of Pathology 3, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, 4SOC Oncologia Medica e Prevenzione Oncologica, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano, Italy, 5Department of Surgical, Medical, Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy Background: Mutations in PIK3CA, an EGFR downstream effector, and the subsequent activation of AKT pathway plays an important role in colorectal carcinogenesis. Considering the frequent co-occurrence of PIK3CA and RAS mutations, conflicting data exist about its impact on prognosis of mCRC patients (pts) and its predictive role to anti-EGFR therapy. However, PI3K inhibitors have been developed and are currently under investigation in mCRC. Methods: Data from mCRC pts treated at Azienda Ospedaliero-Universitaria Pisana from 1 Jan 2005 to 31 Dec 2017, whose tumours had been analysed per clinical practice by MALDI-TOF MassArray were retrieved. Association between PIK3CA mutation and clinico-pathological features was analysed by v2 test; OS curves were estimated with Kaplan-Meier method and compared by log-rank test. Results: Tumours from 90 (17%) out of 542 pts included in this analysis were PIK3CA mutated (mut), most of them in exon 9 (58.9%) or 20 (21.1%). Compared to PIK3CA wild-type (wt) tumours, mut ones were more often RAS mut (P ¼ 0.006), MSI high (P ¼ 0.008), and right-sided (P ¼ 0.0004). Among 53 pts for whom PIK3CA status was available on both primary tumours (PT) and metastasis, the concordance was 92.4%. PIK3CA mutations were not associated with OS (36.4 vs 35.9 mos, HR 1.17, 95%CI 0.85-1.62, p ¼ 0.3), with no difference among those affecting exon 9 and 20 (36.4 vs 27.5 mos, HR 0.77, 95%CI 0.39-1.54, p ¼ 0.44). In RAS/BRAF wt (N 188) and in RAS mut (N 299) subgroup, no difference in terms of OS was found between PIK3CA mut and wt pts (38.1 vs 44.4 mos, HR 1.22, 95%CI 0.60-2.48, p ¼ 0.55 and 27.5 vs 34.4 mos, HR 1.26, 95%CI 0.85-1.86, p ¼ 0.22, respectively), though PIK3CA mut had shorter OS. In BRAF mut subgroup (N 54), PIK3CA mut pts had longer OS compared to PIK3CA wt (not reached vs 14.4 mos, HR 0.37, 95%CI 0.16-0.85, p ¼ 0.09). Among 39 chemorefractory RAS/BRAF wt pts evaluable for response to an anti-EGFR agent, only 2 were exon 9 PIK3CA mut and achieved stable disease. Conclusions: PIK3CA mut tumours displayed specific clinico-pathological features and a strong concordance was found between PT and paired metastases. Interestingly, a different impact on prognosis of PIK3CA mutation in RAS/BRAF wt, RAS mut or BRAF mut mCRC pts was observed and deserves validation. Legal entity responsible for the study: The authors. Funding: Supported by ARCO (Associazione Ricerca e Cure in Oncologia) Foundation. Disclosure: All authors have declared no conflicts of interest.
632P
Patient-derived xenografts (PDX) identify JMJD6 inhibitor as an effective therapeutic medicine in colorectal cancer
F. Ye1, J. You2, L. Xia3, J. Lian3, R. Xiao4, T. Ran4, X. Gao4, J. Li1, X. Zhao1, J. Gao2, H. Lin2, J. Zheng1, W. Liu4 1 Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China, 2Department of Gastrointestinal Surgery, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China, 3Laboratory of Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China, 4 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, China Background: The Jmjc-domain-containing protein 6 (JMJD6) is a member of JmjC oxygenases that contain both arginine demethylase and lysine hydroxylase activities. Overexpression of JMJD6 has been reported to be associated with the development of various types of cancers, such as breast, lung, liver, and colon cancer. The present study aimed to explore the inhibitory effect of the small-molecule JMJD6 inhibitor named WL8 obtained by virtual screening on the progression of colorectal cancer. Methods: WL8 was administered to a mouse bearing xenografts of human colorectal cancer tissue, once every 7 days for 3 times. We analyzed the response of tumors from three patients to the JMJD6 inhibitor (11.5mg/kg, intrapertoneally, i.p.), and to FOLFOX (oxaliplatin 12mg/kg, calcium levifolinate 30mg/kg, 5-fluorouracil 55mg/kg, i.p.) or FOLFIRI (irinotecan 40mg/kg, calcium levifolinate 30mg/kg, 5-fluorouracil 55mg/kg, i.p.), as well as to combined usage of JMJD6 inhibitor and FOLFOX or FOLFIRI in PDX models by recording the tumors sizes every 3 or 4 days for 7 times.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz246.108/5577909 by guest on 27 October 2019
Background: Drug resistance is an important clinical problem affecting the prognosis of colorectal cancer patients with initially unresectable liver metastases. The role of 5hydroxymethylcytosine (5-hmC) in this process is still unknown. Methods: A single-center study was conducted to enroll colorectal cancer patients with initially unresectable liver metastases at Zhongshan Hospital, Shanghai. The 5-hmC levels of each gene locus in circulating-free DNA (cfDNA) were detected using a highly sensitive sequencing method before the patient received any conversion therapy. Eight weeks after conversion therapy, patients with disease progression according to RECIST 1.1 were defined as drug-resistant group, while patients with complete response, partial response and stable disease were defined as the drug-effective group. By using the gene loci with the most significant difference of 5-hmC level, a predictive model (Logistic regression) was established based on machine-learning method. Then, we validated the model. Results: From June 2018 to January 2019, 35 patients were enrolled, including 20 patients in drug-effective group and 15 in drug-resistant group. The predictive model was established using the first 100 significantly different gene loci and 10 loci were included in the model. The internal validation results suggested that the sensitivity (predictive accuracy for drug-resistant patients) and specificity (predictive accuracy for drug-effective patients) were 86.7% and 95.0%, respectively, and the area under the ROC curve is 0.990. Conclusions: Our study screened the gene loci with different 5-hmC level between drug-effective and drug-resistant colorectal cancer patients with initial unresectable liver metastases. Then we established a predictive model for the efficacy of conversion therapy, although this model is still being improved and validated by enrolling more subjects. Clinical trial identification: NCT03679039 09/18/2018. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology