Project description:Background: For the majority of patients of metastatic colorectal cancer (mCRC), systematic chemotherapy has been a choice for palliative treatment. When first-line chemotherapies do not work, targeted therapies are administered. Because of inter-individual genetic and epigenetic variations, patients with mCRC who are treated with these therapies may respond differently. It is of great clinical interest to elucidate response mechanisms that could be utilized in predicting individual response to these treatments. Methods: A highly sensitive technique, the 5hmC-Seal was applied to profile genome-wide 5-hydroxymethylcytosines (5hmC) in 155 cfDNA samples from patients with mCRC recruited for two clinical trials at Zhongshan Hospital, Fudan University in China. Response to systematic chemotherapy and targeted therapy (becacizumab or cetuximab) (CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease) was measured and a 5hmC-based predictive model in cfDNA was developed using a machine learning approach in the PROVE Study (NCT03679039) (n = 100), followed by validation in the METHOD Study (NCT03599947) (n = 55). Results: Genome-wide mapping of 5hmC in patient-derived cfDNA suggested a distinct 5hmC landscape showing tissue origin and gene regulatory relevance. A eleven-gene model involving relevant pathways such as Rap1 signaling pathway, cAMP signaling pathway, Phospholipase D signaling pathway and cGMP-PKG signaling pathway, distinguished patients with mCRC who responded to chemotherapy, regardless of targeted therapy, resectability, or mutation status in the validation samples (AUC=0.77; 95% CI, 0.64-0.90), outperforming RAS mutation status (AUC=0.70; 95% CI, 0.57-0.83). In addition, the 5hmC model also showed a trend of capacity for predicting progression-free survival (PFS) for mCRC. Conclusions: Genome-wide mapping reflected relevant pathways and functional interaction networks implicated in the determination of treatment response for patients with mCRC. The 5hmC-Seal model in cfDNA provided a promising non-invasive method for predicting response to systematic chemotherapy in patients with mCRC, who will be essential for personalized medicine.

Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC.

Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC. This series contains 36 microarrays that are from 18 patients with fresh frozen tissue available from the metastatic site. Pretreatment samples (Bx0) are available for two patients. Pretreatment and post single agent treatment (7-14 days after start of treatment with cetuximab; BxSingle) are available for three patients. Pretreatment and post combination treatment (7-14 days after start of treatment with cetuximab plus carboplatin; BxCombo) are available for eight patients. Two patients have a pretreatment sample, a sample after 7-14 days of treatment with single agent cetuximab, and a third sample 7-14 days on cetuximab plus carboplatin after switching to the combination arm upon progression on the single agent arm. Samples were hybridized with Stratagene common reference spiked with RNA from two breast cancer cell lines (ME16C and MCF-7) on Custom 1x44K Agilent microarrays. Arrays were scanned on an Axon 4000B scanner and analyzed with GenePix Pro software.

Dataset Information

Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable, BRAFV600E metastatic colorectal cancer [dataset 2]

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