However, over the last several years, there have been several studies assessing trends in the treatment of penile squamous cell carcinoma. Data from Joshi and colleagues looking at 1,123 patients with pN positive disease in the NCDB database from 2004-2014 showed that the use of systemic chemotherapy has significantly increased from 38.2% to 47.8%.1 In this study, on multivariable analysis, inguinal lymph node dissection was associated with better overall survival while neither chemotherapy nor radiotherapy was associated with an improvement in overall survival:
In a follow-up to the Joshi et al. study, Dr. Spiess’ team assessed treatment and outcomes in 330 penile squamous cell carcinoma pN positive patients treated at two large tertiary referral centers (Moffitt Cancer Center and Milan).2 The majority of pN2/3 (67%) patients were treated with neoadjuvant systemic chemotherapy while most pN1 (65%) patients were treated with surgery alone. Of the 128 patients treated with surgery alone, 79 (61.7%) were alive at last follow-up with reported 5-yr PFS, CSS, and overall rates of 54.8%, 58.9%, and 54.8%, respectively. Furthermore, on multivariable analysis, no perioperative treatment was associated with improvement in CSS or overall.
Dr. Spiess highlights that to truly impact the disease, one must understand the disease biology. Groundwork to the biologic understanding is the concept of the cancer immunogram, building on two key observations: (i) tumor “foreignness” and (ii) T cell-inhibitory mechanisms. Additionally, there are seven parameters that characterize aspects of cancer-immune interactions for which biomarkers have been identified or are plausible:
There are several molecular pathways in penile cancer, most commonly HPV-induced carcinogenesis. The prevailing model of how HPV infection may progress includes HPV infecting the basal epithelial cells through microtraumas to the skin.3 This is followed by disruption of normal wound healing by HPV oncoproteins occuring through loss of cell polarity and expanding the population of cells harboring HPV genomes. Expression of viral gene products during the differentiation of infected epithelium then results in genome amplification and new infectious viral particles. In addition to increasing cancer risk, persistent infection of HPV is accompanied by viral integration into the host genome and upregulation in the expression of E6 and E7 oncoproteins, resulting in complete loss of polarity control and subsequent invasion and metastasis.
Ultimately, we need actionable mutations in penile cancer to target treatment. In a study of 78 cases of metastatic penile squamous cell carcinoma and 338 cases of metastatic cutaneous squamous cell carcinoma, Jacobs and colleagues performed comprehensive genomic profiling to identify actionable mutations.4 They found that potential targeted therapy opportunities in metastatic penile squamous cell carcinoma cases included alterations in the MTOR pathway (NF1 genomic alterations in 7% and PTEN genomic alterations in 4%) and in the DNA repair pathway (BRCA2 and ATM genomic alterations in 7% each) and tyrosine kinase (EGFR genomic alterations in 6%, and FGFR3 and ERBB2 genomic alterations in 4% each). Previous work from Dr. Spiess’ group has also assessed the prognostic value of PI3K-AKT-mTOR signaling pathway up-regulation among patients with penile squamous cell carcinoma.5 Among 57 patients, HPV in-situ hybridization was positive in 23 patients (40%). PTEN was down-regulated in 43 patients (75%), while phosphorylated-AKT (p-AKT) and phosphorylated-S6 (p-S6) were up-regulated in 27 (47%) and 12 patients (21%), respectively. Furthermore, HPV status was an independent predictor of overall survival (HR 6.99, 95% CI 2.42-20.16) and disease-specific survival (HR 6.74, 95% CI 2.02-22.48).
Additional work from the Moffitt Cancer Center has also evaluated the role of HPV P16 and p53 in penile cancer.6 Among 57 collected specimens of invasive penile cancer, only in p16 negative tumors did p53 positivity predict pN positive disease (OR 4.4, 95% CI 1.04-18.6). On Kaplan-Meier analysis, overall survival was longer in p16 positive tumors (median overall survival 75 versus 27 months), and median CSS was not reached at the time of follow-up. Finally, on multivariable analysis, after adjusting for pN and adjuvant chemotherapy status, p16 was a positive predictor of improved CSS (HR 0.36, 95% CI 0.13-0.99).
Opportunities raised by immunotherapies include the potential benefit of an HPV vaccination as proposed in the following schematic:
Ottenhof and colleagues aimed to identify immunological prognosticators for lymph node metastasis and disease-specific survival among 213 penile cancer patients.7 In this cohort, they found that diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with lymph node metastasis. Additionally, high-risk HPV negativity and diffuse PD-L1 tumor-cell expression was significantly associated with poor DSS and remained so after adjusting for clinical parameters (HR 9.7, p < 0.01 and HR 2.8, p = 0.03, respectively).
A recently reported phase II trial published in JAMA Oncology assessed whether the efficacy of nivolumab is amplified with a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells.8 Among 24 patients with incurable HPV-16 positive cancer (not all patients were penile cancer patients), the overall response rate was 33% (95% CI 19-50%), with a median duration of response of 10.3 months (95% CI 10.3 months to not reached). Median progression-free survival was 2.7 months (95% CI 2.5-9.4 months), and median overall survival was 17.5 months (95% CI 17.5 months to not reached). As such, based on the 33% response rate and overall survival of 17.5 months, further assessment in a randomized trial is warranted. As follows are the ongoing immunotherapy and HPV-directed clinical trials in penile cancer:
Finally, Dr. Spiess’ group has assessed the ability of tumor infiltrating lymphocytes to be grown from penile squamous cell carcinoma cells. In 11 of 12 patients (91.6%), tumor infiltrating lymphocyte growth was achieved in metastatic lymph nodes.
Dr. Spiess concluded his presentation of the molecular basis of penile cancer with the following take-home messages:
- Significant advances have been made in the clinical management of penile cancer
- A fundamental understanding of the molecular pathways implicated in the development and progression of penile cancer is ongoing
- Targeting the HPV pathways as a means of prevention and treatment of penile cancer offers great promise in improving the outcomes of our patients in the years to come
Presented by: Philippe E. Spiess, MD, MS, FRCS(C), FACS, Urologist, Department of GU Oncology and Tumor Biology, Moffitt Cancer Center, Department of Urology, University of South Florida
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 1st Global Society of Rare Genitourinary Tumors Virtual Summit, December 11-12, 2020
- Joshi SS, Handorf E, Strauss D, et al. Treatment Trends and Outcomes for Patients with Lymph Node-Positive Cancer of the Penis. JAMA Oncol. 2018 May 1;4(5):643-649.
- Chipollini J, Necchi A, Spiess PE. Outcomes for patients with node-positive penile cancer: Impact of perioperative systematic therapies and the importance of surgical intervention. Eur Urol. 2018 Aug;74(2):241-242.
- Banks L, Pim D, Thomas M. Human tumour viruses and the deregulation of cell polarity in cancer. Nat Rev Cancer. 2012 Dec;12(12):877-886.
- Jacob JM, Ferry EF, Gay LM, et al. Comparative genomic profiling of refractory and metastatic penile and nonpenile cutaneous squamous cell carcinoma: Implications for Selection of Systemic Therapy. J Urol 2019 Mar;201(3);541-548.
- Azizi M, Tang DH, Verduzco D, et al. Impact of PI3K-AKT-mTOR Signaling pathway up-regulation on prognosis of penile squamous-cell carcinoma: Results from a tissue microarray study and review of the literature. Clin Genitourin Cancer. 2019 Feb;17(1):e80-e91.
- Zargar-Shoshtari K, Spiess PE, Berglund AE, et al. Clinical significance of p53 and p16(ink4a) status in a contemporary North American penile carcinoma cohort. Clin Genitourin Cancer. 2016 Aug;14(4):346-351.
- Ottenhof SR, Djajadiningrat RS, Thygesen HH, et al. The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma. Front Immunol 2018 Jun 11;9:1253.
- Massarelli E, William W, Johnson F, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: A Phase 2 Clinical Trial. JAMA Oncol 2019 Jan 1;5(1):67-73.