4 research outputs found
Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer
CĂĄncer de mama metastĂĄsico; Biomarcadores; CapecitabinaCĂ ncer de mama metastĂ tic; Biomarcadors; CapecitabinaMetastatic breast cancer; Biomarkers; CapecitabinePurpose:
Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received â„2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS.
Patients and Methods:
Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models.
Results:
Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64â1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97â3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54â0.82); H-score â„240 versus <240, HR = 0.77 (0.63â0.93); HERmark positive vs. negative, HR = 0.76 (0.59â0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51â0.81); H-score â„ 240, HR = 0.54 (0.41â0.72); HERmark positive, HR = 0.65 (0.50â0.84)], as did patients with high p95 [p95 â„2.8 relative fluorescence (RF)/mm2, HR = 0.66 (0.50â0.86) vs. p95 < 2.8 RF/mm2, HR = 0.91 (0.61â1.36)].
Conclusions:
PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.This work was supported by Puma Biotechnology Inc. (no grant number is applicable)
Impact of circulating tumor DNA mutant allele fraction on prognosis in RASâmutant metastatic colorectal cancer
Metastatic colorectal cancer; RAS analysis; Prognostic biomarkerCĂĄncer colorrectal en metĂĄstasis; AnĂĄlisis RAS; Biomarcador como pronĂłsticoCĂ ncer colorectal en metĂ stasi; AnĂ lisi RAS; Biomarcador com a pronĂČsticDespite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RASâmutant allele fraction (MAF) in plasma in mCRC. Fortyâseven plasma samples from 37 RASâmutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before firstâ and/or secondâline treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19â9 levels, primary site location, and treatment line) and clinical outcome [progressionâfree survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRIâGOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and firstâline PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRIâGOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5â9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07â5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice.This work was supported partially by the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) and `Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa' grants [FIS PI12-01589 to RS] and RETICC Cancer
Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors
ADN tumoral circulant; Tumor de l'estroma gastrointestinal; ImatinibADN tumoral circulante; Tumor del estroma gastrointestinal; ImatinibCirculating tumor DNA; Gastrointestinal stromal tumor; ImatinibBackground
Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.
Methods
We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).
Results
We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.
Conclusions
ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.This research is supported by a Fero Fellowship Award (C.S.), Asociación Española Contra el Cåncer (J.P. Barcelona) (C.S.), and ISCIII PI16/01371 (C.S.). C.S. and A.V. acknowledge to the Cellex Foundation for providing facilities and equipment. None of the funding bodies had access nor influence in the design, collection, analysis, interpretation and writing the manuscript
Impact of circulating tumor DNA mutant allele fraction on prognosis in RASâmutant metastatic colorectal cancer
Metastatic colorectal cancer; RAS analysis; Prognostic biomarkerCĂĄncer colorrectal en metĂĄstasis; AnĂĄlisis RAS; Biomarcador como pronĂłsticoCĂ ncer colorectal en metĂ stasi; AnĂ lisi RAS; Biomarcador com a pronĂČsticDespite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RASâmutant allele fraction (MAF) in plasma in mCRC. Fortyâseven plasma samples from 37 RASâmutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before firstâ and/or secondâline treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19â9 levels, primary site location, and treatment line) and clinical outcome [progressionâfree survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRIâGOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and firstâline PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRIâGOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5â9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07â5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice.This work was supported partially by the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) and `Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa' grants [FIS PI12-01589 to RS] and RETICC Cancer