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HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53.

Meulendijks D, Tomasoa NB, Dewit L, Smits PH, Bakker R, van Velthuysen ML, Rosenberg EH, Beijnen JH, Schellens JH, Cats A - Br. J. Cancer (2015)

Bottom Line: Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219).In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS.HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands [2] Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands [3] Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.

ABSTRACT

Background: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy.

Methods: Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced.

Results: DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16- disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P<0.001) and HPV-/p16+ tumours (75%, P=0.078). Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219). Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001). In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS.

Conclusions: HPV- tumours are frequently TP53 mutated. HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

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Outcome of patients according to HPV/p16 status. Locoregional control (A) and overall survival (B) of patients according to HPV/p16 status. The P-value represents an overall comparison of the three groups presented in the figure. Pairwise comparisons are given in the text.
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fig2: Outcome of patients according to HPV/p16 status. Locoregional control (A) and overall survival (B) of patients according to HPV/p16 status. The P-value represents an overall comparison of the three groups presented in the figure. Pairwise comparisons are given in the text.

Mentions: Locoregional control and OS were strongly influenced by HPV/p16 status. Figure 2 shows the outcome of patients according to HPV/p16 status. Patients with HPV−/p16− tumours had significantly inferior 3-year LRC (15%) compared with HPV+/p16+ tumours (82%, P<0.001) and HPV−/p16+ tumours (75%, P=0.078). Overall survival at 3 years was 35% for patients with HPV−/p16− tumours compared with 87% for HPV+/p16+ tumours (P<0.001 compared with HPV−/p16−) and 75% for HPV−/p16+ (P=0.219 compared with HPV−/p16−). Among the patients who died during follow-up, in the HPV−/p16− group 5 out of 6 patients (83%) died owing to anal cancer, and in the HPV+/p16+ group, 7 out of 11 patients (64%). The only deceased patient in the HPV−/p16+ group died of anal cancer. We did not identify distinct patterns of local or distant recurrence for HPV+ vs HPV− tumours. Distant recurrence occurred in seven patients (8%) in the HPV+/p16+ group (distant lymph nodes, four patients; liver, two patients; lung, one patient), and in 1 out of 16 patients (6%) in the HPV− group (skeletal). In the subgroup of patients with early-stage tumours who received radiotherapy alone, LRC and OS were also strongly influenced by HPV/p16 status (Supplementary Figure S2). Locoregional control at 3 years was 0% for patients with HPV−/p16− tumours compared with 85% for HPV+/p16+ tumours (P<0.001). Similarly, OS was 33% vs 100% (P=0.002). There were no HPV−/p16+ patients treated with radiotherapy alone.


HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53.

Meulendijks D, Tomasoa NB, Dewit L, Smits PH, Bakker R, van Velthuysen ML, Rosenberg EH, Beijnen JH, Schellens JH, Cats A - Br. J. Cancer (2015)

Outcome of patients according to HPV/p16 status. Locoregional control (A) and overall survival (B) of patients according to HPV/p16 status. The P-value represents an overall comparison of the three groups presented in the figure. Pairwise comparisons are given in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402454&req=5

fig2: Outcome of patients according to HPV/p16 status. Locoregional control (A) and overall survival (B) of patients according to HPV/p16 status. The P-value represents an overall comparison of the three groups presented in the figure. Pairwise comparisons are given in the text.
Mentions: Locoregional control and OS were strongly influenced by HPV/p16 status. Figure 2 shows the outcome of patients according to HPV/p16 status. Patients with HPV−/p16− tumours had significantly inferior 3-year LRC (15%) compared with HPV+/p16+ tumours (82%, P<0.001) and HPV−/p16+ tumours (75%, P=0.078). Overall survival at 3 years was 35% for patients with HPV−/p16− tumours compared with 87% for HPV+/p16+ tumours (P<0.001 compared with HPV−/p16−) and 75% for HPV−/p16+ (P=0.219 compared with HPV−/p16−). Among the patients who died during follow-up, in the HPV−/p16− group 5 out of 6 patients (83%) died owing to anal cancer, and in the HPV+/p16+ group, 7 out of 11 patients (64%). The only deceased patient in the HPV−/p16+ group died of anal cancer. We did not identify distinct patterns of local or distant recurrence for HPV+ vs HPV− tumours. Distant recurrence occurred in seven patients (8%) in the HPV+/p16+ group (distant lymph nodes, four patients; liver, two patients; lung, one patient), and in 1 out of 16 patients (6%) in the HPV− group (skeletal). In the subgroup of patients with early-stage tumours who received radiotherapy alone, LRC and OS were also strongly influenced by HPV/p16 status (Supplementary Figure S2). Locoregional control at 3 years was 0% for patients with HPV−/p16− tumours compared with 85% for HPV+/p16+ tumours (P<0.001). Similarly, OS was 33% vs 100% (P=0.002). There were no HPV−/p16+ patients treated with radiotherapy alone.

Bottom Line: Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219).In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS.HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands [2] Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands [3] Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.

ABSTRACT

Background: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy.

Methods: Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced.

Results: DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16- disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P<0.001) and HPV-/p16+ tumours (75%, P=0.078). Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219). Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001). In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS.

Conclusions: HPV- tumours are frequently TP53 mutated. HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

Show MeSH
Related in: MedlinePlus