Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Grønhøj, Christian; Rasmussen, Jacob; Jong, Robert J. Baatenburg de; James, Jaqueline A; Broglie, Martina A.; Mehanna, Hisham M.; Taberna, Miren; Buchwald, Christian von; Tous, Sara; Huang, Shao Hui; O’Sullivan, Brian; Garset‐Zamani, Martin; Brooks, Jill; Batis, Nikolaos; Fulton-Lieuw, Tessa; Nankivell, Paul; Schache, Andrew; James, Jacqueline; Brakenhoff, Ruud H.; Leemans, C. René; Heideman, Daniëlle A.M.; Bloemena, Elisabeth; Nauta, Irene; Jong, Robert Baatenburg de; Dalianis, Tina; Marklund, Linda; Mirghani, Haïtham; Wagner, Steffen; Wittekindt, Claus; Klußmann, Jens Peter; Wuerdemann, Nora; Quaas, Alexander; Sharma, Shachi Jenny; Maltseva, Margaret; Zimmermann, Philipp; Hoffmann, Markus; Quabius, Elgar Susanne; Däppen, Martina Broglie; Ärztin, Leitende; Bruni, Laia; Mena, Marisa; Morey, Francisca; Alemany, Laia

doi:10.1016/s1470-2045(23)00013-x

Cited by 90 publications

(77 citation statements)

References 28 publications

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“…Furthermore, while p16 is a relatively sensitive and specific surrogate marker for high-risk HPV, it does not always adequately predict response to treatment . Specimens obtained from FNA are often unable to undergo molecular testing and, therefore, unable to differentiate HPV genotypes that may be eligible for de-escalated treatment . This often necessitates further open biopsies via an examination under anesthesia, which in addition to their invasiveness, can also lead to delays in diagnosis .…”

Section: Discussionmentioning

confidence: 99%

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Ferrandino

Chen

Kappauf

et al. 2023

JAMA Otolaryngol Head Neck Surg

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ImportanceThere is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue–modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials.ObjectiveTo establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting.Design, Setting, and ParticipantsThis retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy.Main Outcomes and MeasuresPer-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing.ResultsOf 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days.Conclusions and RelevanceThis cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay’s performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

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Section: Discussionmentioning

confidence: 99%

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Ferrandino

Chen

Kappauf

et al. 2023

JAMA Otolaryngol Head Neck Surg

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“…With only 29.7% of OPC within the study population and the relatively low HPV prevalence, the influence of p16-positive OPC in this population might be negligible. However, with this study, this issue remains unclear [ 27 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Radiotherapy in Patients with Squamous Cell Carcinoma of the Oral Cavity or Oropharynx and Solitary Ipsilateral Lymph Node Metastasis (pN1)—A Prospective Multicentric Cohort Study

Kämmerer

Tribius

Cohrs

et al. 2023

Cancers

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(1) Background: Evaluation of impact of adjuvant radiation therapy (RT) in patients with oral squamous cell carcinoma of the oral cavity/oropharynx (OSCC) of up to 4 cm (pT1/pT2) and solitary ipsilateral lymph node metastasis (pN1). A non-irradiated group with clinical follow-up was chosen for control, and survival and quality of life (QL) were compared; (2) Methods: This prospective multicentric comprehensive cohort study included patients with resected OSCC (pT1/pT2, pN1, and cM0) who were allocated into adjuvant radiation therapy (RT) or observation. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and QL after surgery; (3) Results: Out of 27 centers, 209 patients were enrolled with a median follow-up of 3.4 years. An amount of 137 patients were in the observation arm, and 72 received adjuvant irradiation. Overall survival did not differ between groups (hazard ratio (HR) 0.98 [0.55–1.73], p = 0.94). There were fewer neck metastases (HR 0.34 [0.15–0.77]; p = 0.01), as well as fewer local recurrences (HR 0.41 [0.19–0.89]; p = 0.02) under adjuvant RT. For QL, irradiated patients showed higher values for the symptom scale pain after 0.5, two, and three years (all p < 0.05). After six months and three years, irradiated patients reported higher symptom burdens (impaired swallowing, speech, as well as teeth-related problems (all p < 0.05)). Patients in the RT group had significantly more problems with mouth opening after six months, one, and two years (p < 0.05); (4) Conclusions: Adjuvant RT in patients with early SCC of the oral cavity and oropharynx does not seem to influence overall survival, but it positively affects progression-free survival. However, irradiated patients report a significantly decreased QL up to three years after therapy compared to the observation group.

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“…If positive on p16 IHC, the sample should then be routinely tested for HPV DNA or RNA, especially in regions with low attributable fractions, and/or heavy smokers. The confirmatory HPV testing identifies cases where tumours are p16-positive, but HPV-negative, as they may have poorer prognosis than p16-positive/HPV-positive tumours [12 ▪ ].…”

Section: Initial Investigationsmentioning

confidence: 99%

The role of transoral surgery in the diagnosis of the carcinoma of unknown origin of the head and neck

Mehanna

2023

Current Opinion in Otolaryngology &Amp; Head &Amp; Neck Surgery

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Purpose of reviewThe aim of this article is to update readers on the most recent evidence on the role of trans oral surgery (TOS) in the diagnosis of carcinoma of the unknown primary of the head and neck. Recent findingsTongue base mucosectomy has an important role in identifying the primary in patients who have had negative imaging, PET CT scans and ipsilateral tonsillectomy. In patients with bilateral nodal disease, tongue base mucosectomy should precede tonsillectomy. There are several unanswered questions that remain regarding sequencing of operations and use of intraoperative frozen section.

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Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Cited by 90 publications

References 28 publications

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Adjuvant Radiotherapy in Patients with Squamous Cell Carcinoma of the Oral Cavity or Oropharynx and Solitary Ipsilateral Lymph Node Metastasis (pN1)—A Prospective Multicentric Cohort Study

The role of transoral surgery in the diagnosis of the carcinoma of unknown origin of the head and neck

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