HPV相關OPC：選擇最佳預後人群及最優治療方案

編譯：腫瘤資訊來源：腫瘤資訊專家介紹：

Danny Rischin 教授

Peter MacCallum

癌症中心腫瘤內科主任

JCO副主編

人類乳頭狀瘤病毒（HPV）相關口咽癌（OPC）是美國和澳大利亞最常見的頭頸部鱗狀細胞癌。相較於HPV(-) OPC，HPV（+）OPC具有明顯不同的特徵，包括更高的發病率、更好的生存率與局部控制率、更好的社會經濟學地位、與吸煙及喝酒的相關性更低。

同期放化療聯合治療雖然是局部晚期OPC的標準療法，但對於具有良好預后的HPV（+）OPC患者而言其治療強度可能過大。此外，同期放化療所致的急性與晚期毒性也會對OPC患者的生活質量和功能結局產生不良的影響。因此，我們的研究旨在尋找具有良好預后的HPV（+）OPC患者以作為「減強度試驗」的受試人群。Ang等研究者基於HPV感染狀態、吸煙情況、T分期及N分期將OPC患者分類成低、中、高危組。O』Sullivan等研究者制定了對於HPV（+）OPC患者的「國際OPC合作網路分期（ICON-S）」，該分期顯示出優於傳統TNM分期的高效性。以上兩項研究都能篩選出HPV（+）OPC的低危人群，而這些患者適用於更加保守的減強度治療策略，比如單純手術、誘導化療后低劑量放療、放療伴或不伴低強度化療/西妥昔單抗/免疫調定點抑製劑等等。我們利用Peter Mac 癌症中心的研究隊列對上述危險度模型進行了驗證，ICON-S分期具有最佳的危險度分辨能力，其次是Ang危險評分，最次是第七版TNM分期。

HPV（+）OPC患者依照預后不同而進行的精確分層及治療有賴於一些免疫相關的生物標記（如p16）。為了尋找並闡明這些生物標記物，Peter Mac 癌症中心實施了免疫學相關的探究性研究。這些研究著眼於腫瘤浸潤淋巴細胞（TIL）的CD8染色以及腫瘤細胞的PD-L1染色。腫瘤基質細胞中的CD8（+）TILs≥ 30%與更高的總生存期相關。對於HPV（+）OPC人群及其所有ICON-S分期亞組，免疫細胞PD-L1（+）≥ 5%與更高的總生存期相關；且該相關性只在腫瘤上皮細胞中發現，而在腫瘤基質細胞及腫瘤周圍免疫細胞中未發現。我們的研究確認了上皮細胞的PD-L1染色與腫瘤細胞（通過p16識別）的PD-L1染色具有顯著的差異。大多數PD-L1（+）免疫細胞為CD8（-）的TILs。而一部分PD-L1（+）免疫細胞為CD8（+）的TILs，並很可能表達為其他免疫細胞類型。

這些研究發現有助於選擇具有良好預后的HPV（+）OPC患者，並以此為「減強度試驗」的提供受試人群。而HPV（+）OPC的免疫分型分析可以幫助篩選該類型OPC患者。

英文原文：

Human papilloma virus associated oropharyngeal cancer – defining favourable prognostic groups and better treatment strategies

Danny Rischin

Director, Department of Medical Oncology

Peter MacCallum Cancer Centre

Human papilloma virus (HPV) associated oropharyngeal cancer (OPC) is the most common head and neck squamous cell carcinoma in the U.S. and Australia. HPV(+) OPC has distinct characteristics compared with HPV(-) OPC, including an increasing incidence, improved survival and locoregional control, higher socioeconomic status and lower associations with alcohol/tobacco consumption.

Although concomitant chemoradiation is the standard of care for locoregionally advanced OPC, it may be more intensive than required for the subgroup of HPV(+) OPC patients with good prognosis. Besides, high levels of acute and late toxicity of the standard chemoradiation have adverse effects on quality of life and functional outcomes of OPC patients. Therefore, it is worthy of investigation to identify the HPV(+) OPC patients with an excellent prognosis that may be candidates for de-intensification trials. Ang et al. classified OPC patients as having a low, intermediate, or high risk of death based on HPV status, pack-years of tobacco smoking, and T&N stage. O』Sullivan et al. developed the ICON-S Stage Classification for HPV(+) OPC, which showed better efficacy than the traditional TNM stage system. Low risk groups as defined by Ang et al. and ICON-S stage are suitable for more conservative de-intensification strategies, such as surgery alone, induction chemotherapy followed by reduced dose radiation, radiation with or without less intensive chemotherapy/cetuximab/immune checkpoint inhibitor. In the validation based on the Peter Mac cohort, ICON-S stage had the best ability of discrimination, followed by the Ang risk score, and finally the 7th edition TNM staging system.

An immunoprofiling study from the Peter Mac Cancer Center was performed to identify and characterise immune biomarkers (e.g., p16) that accurately prognostically stratify populations of HPV(+) OPC patients in order to accurately guide treatment. Further investigation focused on the tumor infiltrating lymphocytes (TIL) CD8 staining and the tumor cell PD-L1 staining. CD8(+) TILs in stromal/tumoural ≥ 30% is associated with better overall survival (OS). PD-L1(+) ≥ 5% in tumoural/intraepithelial immune cell, but not tumoural, stromal or peritumoural immune cells, is associated with an improved OS for HPV(+) OPC and all their ICON-S stage subgroups. Our study confirmed that PD-L1 intra-epithelial immune cell staining was distinct from PD-L1 tumour (as identified by p16) staining. A proportion of the PD-L1(+) immune cells was CD8(+) TILs – but the majority was CD8(-) – and was likely to represent other immune cell populations.

These findings help to select the best prognosis HPV(+) OPC patients and hence the candidates for de-intensification strategies. Immunophenotyping of HPV(+) OPC may assist in identifying patients with an excellent prognosis for novel de-intensification trials.

版權聲明版權屬腫瘤資訊所有。歡迎個人轉發分享，其他任何媒體、網站如需轉載或引用本網版權所有內容，須獲得授權，且在醒目位置處註明「轉自：良醫匯-腫瘤醫生APP」。