Sensitive MRD Detection from Lymphatic Fluid after Surgery in HPV-Associated Oropharyngeal Cancer

Author:

Earland Noah12ORCID,Semenkovich Nicholas P.23ORCID,Ramirez Ricardo J.4ORCID,Gerndt Sophie P.5ORCID,Harris Peter K.1ORCID,Gu Zhuosheng6ORCID,Hearn Andrew I.4ORCID,Inkman Matthew1ORCID,Szymanski Jeffrey J.1ORCID,Whitfield Damion6ORCID,Wahle Benjamin M.4ORCID,Xu Zhongping7ORCID,Chen Kevin1ORCID,Alahi Irfan18,Ni Gabris1ORCID,Chen Andrew1ORCID,Winckler Wendy6ORCID,Zhang Jin129ORCID,Chaudhuri Aadel A.12891011ORCID,Zevallos Jose P.712ORCID

Affiliation:

1. 1Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

2. 2Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri.

3. 3Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

4. 4Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri.

5. 5Division of Otolaryngology-Head and Neck Surgery, Allegheny Health Network, Pittsburgh, Pennsylvania.

6. 6Droplet Biosciences, Inc., Cambridge, Massachusetts.

7. 7Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

8. 8Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, Missouri.

9. 9Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

10. 10Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.

11. 11Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri.

12. 12Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Abstract

Abstract Purpose: Our goal was to demonstrate that lymphatic drainage fluid (lymph) has improved sensitivity in quantifying postoperative minimal residual disease (MRD) in locally advanced human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) compared with plasma, and leverage this novel biofluid for patient risk stratification. Experimental Design: We prospectively collected lymph samples from neck drains of 106 patients with HPV (+) OPSCC, along with 67 matched plasma samples, 24 hours after surgery. PCR and next-generation sequencing were used to quantify cancer-associated cell-free HPV (cf-HPV) and tumor-informed variants in lymph and plasma. Next, lymph cf-HPV and variants were compared with TNM stage, extranodal extension (ENE), and composite definitions of high-risk pathology. We then created a machine learning model, informed by lymph MRD and clinicopathologic features, to compare with progression-free survival (PFS). Results: Postoperative lymph was enriched with cf-HPV compared with plasma (P < 0.0001) and correlated with pN2 stage (P = 0.003), ENE (P < 0.0001), and trial-defined pathologic risk criteria (mean AUC = 0.78). In addition, the lymph mutation number and variant allele frequency were higher in pN2 ENE (+) necks than in pN1 ENE (+) (P = 0.03, P = 0.02) or pN0-N1 ENE (−) (P = 0.04, P = 0.03, respectively). The lymph MRD-informed risk model demonstrated inferior PFS in high-risk patients (AUC = 0.96, P < 0.0001). Conclusions: Variant and cf-HPV quantification, performed in 24-hour postoperative lymph samples, reflects single- and multifeature high-risk pathologic criteria. Incorporating lymphatic MRD and clinicopathologic feature analysis can stratify PFS early after surgery in patients with HPV (+) head and neck cancer.

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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