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Proffered paper and Mini oral mixed session on Head and neck

267O - Distinct phenotypes of locoregionally advanced (LA-NPC) harbor disparate survival outcomes and are associated with germline variants

Date

21 Nov 2020

Session

Proffered paper and Mini oral mixed session on Head and neck

Presenters

Enya Ong

Citation

Annals of Oncology (2020) 31 (suppl_6): S1347-S1354. 10.1016/annonc/annonc360

Authors

E. Ong1, A.Y.L. Sim2, L. Huang3, K.P. Low2, W. Wai Yee1, D. Susanti2, H. Wang2, T.W.K. Tan1, K.W. Fong1, Y.L. Soong1, G.S. Tan4, T.K.H. Lim5, J.T.S. Wee1, D.W.T. Lim6, N.G. Iyer7, J.S.G. Hwang5, M. Abazeed8, J.X. Bei9, M.L.K. Chua1

Author affiliations

  • 1 Division Of Radiation Oncology, NCCS - National Cancer Centre Singapore, 169610 - Singapore/SG
  • 2 Division Of Medical Sciences, NCCS - National Cancer Centre Singapore, 169610 - Singapore/SG
  • 3 Division Of Radiation Oncology, Guangxi Medical University Cancer Hospital, 530021 - Guangxi/CN
  • 4 Department Of Molecular Pathology, Singapore General Hospital, 169608 - Singapore/SG
  • 5 Department Of Anatomical Pathology, Singapore General Hospital, 169608 - Singapore/SG
  • 6 Division Of Medical Oncology, NCCS - National Cancer Centre Singapore, 169610 - Singapore/SG
  • 7 Division Of Surgical Oncology, NCCS - National Cancer Centre Singapore, 169610 - Singapore/SG
  • 8 Department Of Radiation Oncology, Northwestern University, 60208 - IL/US
  • 9 Center For Precision Medicine, Sun Yat-sen University, 510080 - Guangzhou/CN
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Resources

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Abstract 267O

Background

LA-NPC can be subtyped by ascending (A; T3-4N0-1), descending (D; T1-2N2-3) and ascending-descending (AD; T3-4N2-3) at diagnosis, depending on the extent of tumor spread. These phenotypes differ by prognoses, but germline and somatic molecular drivers underpinning their tumorigenesis are unknown. We aimed to validate the A and AD subtypes of LA-NPC and investigate for germline variants that are associated with them.

Methods

We utilized a cohort of 255 patients with biopsy-proven, non-metastatic, T3-4 NPC (AJCC/UICC 8th edition). Association of clinical covariates were tested by Cox regression. Germline profiling was conducted by whole exome sequencing (100x; Illumina NovaSeq) and variants were shortlisted based on known/predicted pathogenicity. The differential prevalence of variants was tested using Fisher’s exact test.

Results

Median follow-up duration of the cohort was 79 (IQR: 66-90) mo; median age was 49.4 (43.2-58.1) y. We identified 108 (42.3%) A- and 147 (57.6%) AD-subtype in our cohort. 55 (50.9%) and 35 (32.4%) of the A-subtype patients compared to 64 (43.5%) and 75 (51.0%) in the AD-subgroup received chemoradiotherapy (CRT) alone and CRT+induction/adjuvant chemotherapy, respectively. High EBV DNA titer of >4000 copies were more frequent in the AD- than A-subgroup (50.0% vs 31.2%, P = 0.0141). 5-y DFS differed between the A and AD subtypes (85.1% [95% CI: 78.2-92.7] vs 67.0% [59.2-75.8%], P <0.001); the AD-subtype was significantly associated with worse DFS (HR 3.10 [1.54-6.23], P = 0.00147) after adjustment for age, EBV DNA and T4-status. Next, we observed germline variants in hallmark-of-cancer genes (FAT1 [N=46; 18.0%] and NOTCH1 [N=13; 5.1%]), DNA repair genes (SRSF6 [N=13; 5.1%] and POLD1 [N=14; 5.5%]) and genes with known association to NPC (MST1R [N=13; 5.1%] and SYNE1[N=50; 19.6%]). Of them, TGFBR2 variants were significantly associated with the unfavorable AD-subtype (OR 3.68 [1.06-15.3], P = 0.041).

Conclusions

We have shown that the AD-subtype in patients with LA-NPC is associated with an inferior DFS. The TGFBR2germline variants may be associated with the susceptibility of this unfavorable phenotype.

Clinical trial identification

CIRB Ref. No.: 2019/2177.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Medical Research Council.

Disclosure

All authors have declared no conflicts of interest.

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