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Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma- Beyond the Abstract

Penile squamous cell carcinoma (PSCC) is among the rarest genitourinary cancers, especially in high-income countries, nevertheless, it is burdened with poor survival outcomes.1 Among the risk factors associated with PSCC development, human papillomavirus (HPV) infection is the linchpin of the worldwide spread of this tumor.2, 3 Particularly, HPV DNA is identified in almost 50% of penile tumors with more than 80% of such cases being attributable to high-risk HPV-16 genotype infection.4, 5 Adjuvant chemotherapy is the recommended treatment for patients with node-positive PSSC, while radiotherapy (RT) is only proposed for selected cases.6, 7 Some evidence reported better survival outcomes for PSCC patients harboring HPV infection as compared to those who are HPV-negative,8, 9 however the effects that HPV infection has on adjuvant therapies’ outcomes is still unclear.


In our recently published article,10 we reported results of a multi-institutional database on PSCC patients who underwent inguinal lymph node dissection (ILND), evaluating whether the presence of HPV infection could be a predictor of response to perioperative RT. Patients with HPV+ PSCC had a lower burden of inguinal lymph node metastases (ILNM), identified both as pathologic N stage (p < 0.001) and ILNM density (p < 0.001), as compared to HPV-negative patients. Moreover, despite we found a similar overall survival (OS) rate between HPV+ and HPV– patients regardless of adjuvant treatment used, the restricted mean survival time (RMST) analyses showed an OS benefit for HPV+  patients at 3 yr (3.5 mo, 95% confidence interval [CI] 1.6–5.3; p < 0.001), 5 yr (7.2 mo, 95% CI 3.0–11.4; p = 0.001), and 7 yr (9.7 mo, 95% CI 2.1–16.6; p = 0.006), without significant differences at 10 yr (8.3 mo, 95% CI –3.7 to 20.2; p = 0.2). Conversely, when considering only patients treated with perioperative RT, HPV+ status was associated with longer median OS (p = 0.015) and longer RMST at 3 yr (9.5 mo, 95% CI 5.7– 13.2; p < 0.001), 5 yr (23.3 mo, 95% CI 15.5–31.1; p < 0.001), 7 yr (32.3 mo, 95% CI 17.8–46.9; p < 0.001), and 10 yr (39.1 mo, 95% CI 11.8–66.4; p = 0.005) of follow-up. In order to understand the biology underlying these different responses a comprehensive genomic profiling (CGP) assay on tumor tissues was carried out. Particularly, PI3KCA was the most common altered gene in HPV+ patients (38.7% vs. 17%) followed by KMT2D (25.8% vs 3%), while TP53 (75.2% vs. 15%), CDKN2A (65% vs 1%), and TERT (promoter region; 60.2% vs 9%) were mostly altered in HPV-negative tumor. Moreover, the median tumor mutation burden (TMB) was higher in HPV+ than in HPV– tumors (5.2 mutations/Mb vs. 3.2 mutations/Mb).

Despite we were unable to separately analyze the impact of preoperative and postoperative treatments and the lack of information regarding the use and type of adjuvant chemo-sensitizing agents used as well as the fields for RT treatment, we identified a novel tumor-related factor for the selection of the most suitable candidates for multidisciplinary treatment after surgery. Particularly, we provided results suggesting that the higher TMB and the lower TP53 mutation frequency for HPV+ tumors could have a role in PSCC sensitivity to perioperative RT. Finally, the latter feature could be introduced as a tool to stratify patients in randomized clinical trials.

Written by: Giuseppe Basile,1 Marco Bandini,1 Philippe E. Spiess2 and Andrea Necchi1,3

  1. San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy;
  2. Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  3. Fondazione IRCCS Istituto Nazionale dei Tumori
References

  1. S. Misra, A. Chaturvedi, and N. C. Misra, “Penile carcinoma: A challenge for the developing world,” Lancet Oncology, vol. 5, no. 4. Lancet Oncol, pp. 240–247, 01-Apr-2004.
  2. D. M. Backes, R. J. Kurman, J. M. Pimenta, and J. S. Smith, “Systematic review of human papillomavirus prevalence in invasive penile cancer,” Cancer Causes and Control, vol. 20, no. 4. Cancer Causes Control, pp. 449–457, May-2009.
  3. M. Bandini et al., “Contemporary Treatment Patterns and Outcomes for Patients with Penile Squamous Cell Carcinoma: Identifying Management Gaps to Promote Multi-institutional Collaboration,” Eur. Urol. Oncol., Sep. 2020.
  4. D. A. M. Heideman et al., “Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma,” J. Clin. Oncol., vol. 25, no. 29, pp. 4550–4556, Oct. 2007.
  5. T. B. Olesen et al., “Prevalence of human papillomavirus DNA and p16 INK4a in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis,” Lancet Oncol., vol. 20, no. 1, pp. 145–158, Jan. 2019.
  6. S. B. Williams et al., “Impact of Centralizing Care for Genitourinary Malignancies to High-volume Providers: A Systematic Review,” European Urology Oncology, vol. 2, no. 3. Elsevier B.V., pp. 265–273, 01-May-2019.
  7. M. Bandini, F. Pederzoli, and A. Necchi, “Neoadjuvant chemotherapy for lymph node-positive penile cancer: Current evidence and knowledge,” Current Opinion in Urology, vol. 30, no. 2. Lippincott Williams and Wilkins, pp. 218–222, 01-Mar-2020.
  8. F. Lohaus et al., “HPV16 DNA status is a strong prognosticator of loco-regional control after postoperative radiochemotherapy of locally advanced oropharyngeal carcinoma: Results from a multicentre explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG),” Radiother. Oncol., vol. 113, no. 3, pp. 317–323, Dec. 2014.
  9. S. R. Ottenhof, R. S. Djajadiningrat, J. de Jong, H. H. Thygesen, S. Horenblas, and E. S. Jordanova, “Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status,” J. Urol., vol. 197, no. 3 Part 1, pp. 690–697, Mar. 2017.
  10. M. Bandini et al., “Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma,” Eur. Urol. Oncol., Nov. 2020.
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