Cancer Res Treat.  2022 Jan;54(1):259-268. 10.4143/crt.2021.010.

Absolute Neutrophil Count after the First Chemotherapy Cycle as a Surrogate Marker for Treatment Outcomes in Patients with Neuroblastoma

Affiliations
  • 1Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 2Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 3Clinical Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam, Korea
  • 4Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea

Abstract

Purpose
We performed this study to determine whether the degree of neutropenia after the first chemotherapy cycle can be used as a surrogate marker of individual susceptibility to chemotherapeutic agents affecting treatment outcome in patients with neuroblastoma.
Materials and Methods
The study included 313 patients who received the first cycle chemotherapy with a CEDC (cisplatin+etoposide+doxorubicin+cyclophosphamide) regimen and had absolute neutrophil count (ANC) data available. The cumulative incidences of progression and treatment-related mortality (TRM) were estimated. To identify genetic variations associated with the ANC, a genome-wide association study (GWAS) was performed.
Results
An ANC of 32.5/μL was determined as the cutoff point to categorize patients into the good and poor prognosis subgroups in terms of progression. Patients with a high nadir ANC had a higher cumulative incidence of progression than those with a low nadir ANC (p < 0.001). In multivariate analysis, high nadir ANC, age, bone marrow involvement, and unfavorable histology were poor prognostic factors. With regard to the TRM, patients with a low nadir ANC (ANC < 51.0/μL) had a higher cumulative incidence of TRM than those with a high nadir ANC (p=0.010). In GWAS, single-nucleotide polymorphisms of LPHN2 and CRHR1 were significantly associated with the nadir ANC.
Conclusion
In neuroblastoma patients, the degree of neutropenia after the first chemotherapy cycle can be used as a surrogate marker to predict an individual’s susceptibility to chemotherapeutic agents. Tailoring of treatment based on the degree of neutropenia needs to be considered.

Keyword

Neuroblastoma; Neutropenia; Treatment outcome; Germline; Genome-wide association study

Figure

  • Fig. 1 Survival outcomes according to the absolute neutrophil count (ANC) group. Cumulative incidence of progression/treatment-related mortality, event-free survival, and overall survival based on an ANC cutoff value of 32.5/μL in all patients (A), in patients aged ≥ 2 years (B), and in high-risk patients (C).

  • Fig. 2 Tumor response according to the absolute neutrophil count (ANC) group. The percentage of residual tumor volume at the first response evaluation in all patients (A), in high-risk patients (B), and in patients with undifferentiated (UD) or poorly differentiated (PD) neuroblastoma (C).

  • Fig. 3 Cumulative incidence of treatment-related mortality (TRM) according to the absolute neutrophil count (ANC) group. An ANC of 51.0/μL was selected as an optimal cutoff point for the cumulative incidence of TRM, and patients in the ANC > 51.0/μL group showed a lower 5-year cumulative incidence of TRM than those in the ANC ≤ 51.0/μL group (1.3%±0.02% vs. 9.4%±0.04%, respectively) in all patients (A) and in high-risk patients (B).

  • Fig. 4 Manhattan plot of the genome-wide association study. (A) Results of the genome-wide association analyses of common single- nucleotide polymorphisms (SNPs) (minor allele frequency > 0.05) associated with the absolute neutrophil count represented as a Manhattan plot. The X-axis represents the SNP markers on each chromosome. (B) Regional association plots at the RPTN locus. Regional association plots, including both genotypes and SNPs of the LPHN2, were generated using LocusZoom within 400 kb.


Reference

References

1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007; 369:2106–20.
Article
2. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003; 3:203–16.
Article
3. Hero B, Simon T, Spitz R, Ernestus K, Gnekow AK, Scheel-Walter HG, et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol. 2008; 26:1504–10.
Article
4. Moen EL, Godley LA, Zhang W, Dolan ME. Pharmacogenomics of chemotherapeutic susceptibility and toxicity. Genome Med. 2012; 4:90.
Article
5. Roden DM, McLeod HL, Relling MV, Williams MS, Mensah GA, Peterson JF, et al. Pharmacogenomics. Lancet. 2019; 394:521–32.
Article
6. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990; 336:225–9.
Article
7. Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015; 33:1235–42.
Article
8. Bagatell R, McHugh K, Naranjo A, Van Ryn C, Kirby C, Brock P, et al. Assessment of primary site response in children with high-risk neuroblastoma: an international multicenter study. J Clin Oncol. 2016; 34:740–6.
Article
9. Lee JW, Lee S, Cho HW, Ma Y, Yoo KH, Sung KW, et al. Incorporation of high-dose (131)I-metaiodobenzylguanidine treatment into tandem high-dose chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma: results of the SMC NB-2009 study. J Hematol Oncol. 2017; 10:108.
Article
10. Sung KW, Son MH, Lee SH, Yoo KH, Koo HH, Kim JY, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma: results of SMC NB-2004 study. Bone Marrow Transplant. 2013; 48:68–73.
Article
11. Laska E, Meisner M, Wanderling J. A maximally selected test of symmetry about zero. Stat Med. 2012; 31:3178–91.
Article
12. Kim HT. Cumulative incidence in competing risks data and competing risks regression analysis. Clin Cancer Res. 2007; 13:559–65.
Article
13. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010; 26:2336–7.
Article
14. Kishida Y, Kawahara M, Teramukai S, Kubota K, Komuta K, Minato K, et al. Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03. Br J Cancer. 2009; 101:1537–42.
Article
15. Ma RM, Chen CZ, Zhang W, You J, Huang DP, Guo GL. Prognostic value of chemotherapy-induced neutropenia at the first cycle in invasive breast cancer. Medicine (Baltimore). 2016; 95:e3240.
Article
16. Kasi PM, Kotani D, Cecchini M, Shitara K, Ohtsu A, Ramanathan RK, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016; 16:467.
Article
17. Chen Y, Wang Y, Shi Y, Dai G. Timing of chemotherapy-induced neutropenia predicts prognosis in metastatic colon cancer patients: a retrospective study in mFOLFOX6-treated patients. BMC Cancer. 2017; 17:242.
Article
18. Sung L, Aplenc R, Alonzo TA, Gerbing RB, Wang YC, Meshinchi S, et al. Association between prolonged neutropenia and reduced relapse risk in pediatric AML: a report from the children’s oncology group. Int J Cancer. 2016; 139:1930–5.
Article
19. Alexander S, Pole JD, Gibson P, Lee M, Hesser T, Chi SN, et al. Classification of treatment-related mortality in children with cancer: a systematic assessment. Lancet Oncol. 2015; 16:e604–10.
Article
20. White GR, Varley JM, Heighway J. Genomic structure and expression profile of LPHH1, a 7TM gene variably expressed in breast cancer cell lines. Biochim Biophys Acta. 2000; 1491:75–92.
Article
21. Eng L, Ibrahimzada I, Jarjanazi H, Savas S, Meschian M, Pritchard KI, et al. Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines. BMC Med Genomics. 2011; 4:18.
Article
22. Perez-Ortiz AC, Ramirez I, Cruz-Lopez JC, Villarreal-Garza C, Luna-Angulo A, Lira-Romero E, et al. Pharmacogenetics of response to neoadjuvant paclitaxel treatment for locally advanced breast cancer. Oncotarget. 2017; 8:106454–67.
Article
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