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Abstract
We conducted a prospective phase II study on whether extended-field irradiation (EFI) confers survival benefits depending on hypoxic markers in locally advanced uterine cervical cancer (LAUCC). RNA-seq was performed to identify immune and hypoxic gene signatures. A total of 288 patients were randomized to either EFI or pelvic radiotherapy (PRT). All patients completed chemoradiotherapy. Overall, significantly higher 5-year para-aortic recurrence free survival (PARFS) rate occurred in EFI (97.6%) than in PRT group (87.2%), with marginal tendency to improve disease-free survival (DFS; 78% vs 70%, P = .066). Subgroup analyses were performed based on carbonic anhydrase 9 (CA9)-only positive, CA9/hypoxia-inducible factor (HIF) double positive and CA9 negative. In the CA9-only positive, EFI successfully increased 5-year PARFS (100% vs 76.4%, P = .010), resulting in significantly improved long-term DFS (85.7% vs 54.7%, P = .023) compared to the PRT, while there was no such benefit of EFI in the CA9/HIFs double positive. RNA-seq analysis identified distinct immunehigh subgroup with negative correlation with hypoxia gene signatures (R = -.37, P < .01), which showed a higher 5-year DFS than the immunelow (P = .032). Hypoxia-related genes were upregulated in the CA9/HIFs double positive compared to CA9 negative (P < .05). Only 17.4% of patients in CA9-negative group showed immunelow signatures, while 40.0% of patients in the double-positive group exhibited immunelow signatures. In conclusion, EFI improved PARFS significantly in all patients, but therapeutic efficacy of EFI in terms of improved DFS was solely observed in CA9-only positive LAUCC, and not in CA9/HIFs double-positive subgroup. RNA-seq analysis suggested that hypoxia-induced immunosuppression may be related to treatment resistance in LAUCC.

Affiliations

Meesun Yoon 1, Hyo Kyung Lee 2, Eun Young Park 3, Jin Hee Kim 4, Jong Hoon Lee 5, Young Seok Kim 6, Hak Jae Kim 7, Hunjung Kim 8, Chong Woo Yoo 3, Sun Lee 9, Eun Kyung Hong 3, Tae Hyun Kim 3, Tae-Sung Kim 3, Sang-Soo Seo 3, Sokbom Kang 3, Suk-Joon Chang 10, Hye Jin Shin 3, Tung Nguyen Thanh Uong 1, Semin Lee 2, Joo-Young Kim 3
1Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea.
2Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea.
3Research Institute and Hospital, National Cancer Center, Goyang, South Korea.
4Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, South Korea.
5Department of Radiation Oncology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University, Seoul, South Korea.
6Department of Radiation Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea.
7Department of Radiation Oncology, Seoul National University, College of Medicine, Seoul, South Korea.
8Department of Radiation Oncology, Inha University Hospital, Inha University, School of Medicine, Incheon, South Korea.
9Department of Pathology, College of Medicine, Kyung Hee University, Seoul, South Korea.
10Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, South Korea.