Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers

Hitomi Sumiyoshi Okuma; Kan Yonemori; Yuki Kojima; Maki Tanioka; Kazuki Sudo; Emi Noguchi; Susumu Hijioka; Keiko Wakakuwa; Ken Kato; Akihiro Hirakawa; Aya Kuchiba; Takashi Kubo; Hitoshi Ichikawa; Akihiko Yoshida; Yasushi Yatabe; Kenichi Nakamura; Hiroyuki Mano; Noboru Yamamoto; Yasuhiro Fujiwara

doi:10.3389/fonc.2021.732525

Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers

Front Oncol. 2021 Nov 24:11:732525. doi: 10.3389/fonc.2021.732525. eCollection 2021.

Authors

Hitomi Sumiyoshi Okuma^{1

2}, Kan Yonemori¹, Yuki Kojima¹, Maki Tanioka¹, Kazuki Sudo¹, Emi Noguchi¹, Susumu Hijioka³, Keiko Wakakuwa², Ken Kato⁴, Akihiro Hirakawa⁵, Aya Kuchiba⁶, Takashi Kubo⁷, Hitoshi Ichikawa⁷, Akihiko Yoshida⁸, Yasushi Yatabe⁸, Kenichi Nakamura², Hiroyuki Mano⁹, Noboru Yamamoto¹⁰, Yasuhiro Fujiwara^{1

11}

Affiliations

¹ Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
² Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
³ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁴ Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁵ Division of Biostatistics and Data Science, Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
⁶ Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan.
⁷ Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
⁸ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁹ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
¹⁰ Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
¹¹ Chief Executive, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

Abstract

Purpose: Patients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.

Patients and methods: Rare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.

Results: Ninety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.

Conclusion: Plasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.

Clinical registration: [https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

Keywords: CtDNA (circulating tumor DNA); precision medicine; rare cancer; soft tissue sarcoma; targeted therapy.