This article was downloaded by: [University of California, San Diego] On: 05 September 2015, At: 08:08 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London, SW1P 1WG
Expert Opinion on Drug Discovery Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/iedc20
Novel targeted therapies for the treatment of penile cancer a
a
b
Gautum Agarwal MD , Shilpa Gupta MD & Philippe E Spiess MD MS FACS Associate member a
Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, FL, USA
b
Moffitt Cancer Center, Department of Genitourinary Oncology, 12902 Magnolia Drive office 12538, Tampa, FL 33612, USA +1 813 745 8343; +1 813 745 8494; Published online: 04 Jun 2014.
Click for updates To cite this article: Gautum Agarwal MD, Shilpa Gupta MD & Philippe E Spiess MD MS FACS Associate member (2014) Novel targeted therapies for the treatment of penile cancer, Expert Opinion on Drug Discovery, 9:8, 959-968 To link to this article: http://dx.doi.org/10.1517/17460441.2014.925875
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Review
Novel targeted therapies for the treatment of penile cancer
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Gautum Agarwal, Shilpa Gupta & Philippe E Spiess† Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, FL, USA
1.
Introduction
2.
Molecular markers and targets
3.
Expert opinion
Introduction: The treatment of penile cancer has changed over the past decade in that it was primarily a surgically managed disease and those with locally advanced or metastatic disease uniformly had a very poor prognosis. However, with the use of better traditional systemic chemotherapeutic agents in the neoadjuvant and adjuvant settings, the disease-specific survival and general outlook has improved. However, there is still a large group of patients who will progress even while on systemic therapy. It is in those patients where the application of targeted therapies has been investigated with some experiencing partial or even complete responses. With the improvement seen in patients with chemotherapy refractory disease, the application of novel targeted agents in the neoadjuvant setting may have a resultant positive impact on patient survival. Areas covered: This review includes research pertaining to targeted therapies, biomarkers and signaling pathways involved with penile cancer. The article was based on a literature search using the keywords ‘penile cancer’ and ‘targeted therapies’. Expert opinion: Penile cancer at the advanced stages of the disease has a high mortality. The utilization of novel targeted therapies in these situations is warranted in combination with, or sequentially with, traditional cytotoxic chemotherapy to improve the patient survival rate. Personalized therapy is nearly here for penile cancer and should be made real within the next decade. Keywords: biomarkers, human papillomavirus, penile cancer, targeted therapy Expert Opin. Drug Discov. (2014) 9(8):959-968
1.
Introduction
In the USA, there will be ~ 1640 new cases of penile cancer diagnosed in 2014 and 320 patients will die from this disease [1]. Compared to other cancers, there is a very low incidence of penile cancer in the USA, < 1 per 100,000 males [2], due in part to the high prevalence of males who undergo neonatal circumcision (~ 55%) and improved penile hygiene [3]. Among those patients who develop penile cancer, ~ 20% will have metastatic disease on presentation, with distant metastasis present in 2.5% of patients [4]. Survival for someone with penile cancer is almost entirely dependent on the presence or absence of metastasis in the regional lymph nodes [5]. In the case of patients with palpable mobile inguinal lymph nodes that are < 4 cm, surgical excision is considered the standard of care and does provide some patients with cure. When the patient’s inguinal lymph nodes are fixed, > 4 cm, or there is involvement of pelvic lymph nodes with metastatic cancer, achievement of cure becomes near impossible; however, with the implementation of multimodal treatment involving systemic chemotherapy, surgery and radiation, there have been published series observing patients with a reliable treatment response [6]. With the advent of novel targeted therapeutic agents, patients who have failed to respond to traditional chemotherapeutic agents may have a response. Additional studies on the combination of these targeted agents with other antineoplastic drugs 10.1517/17460441.2014.925875 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted
959
G. Agarwal et al.
Article highlights. . .
.
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
.
.
EGFR is overexpressed in the majority of penile cancers, making this an excellent target for therapeutic benefit. The epithelial-to-mesenchymal transition explains the mechanisms of action involved with penile cancer tumor invasion, laying out potential targets for therapy. The activity of anti-EGFR agents is decreased when a patient expresses KRAS mutation, making this an important biomarker in selecting patients for therapy. COX-2 inhibition may play a role in the chemoprevention and treatment of penile cancer. The combination of COX-2 inhibition with other targeted therapies demonstrates a promising approach in treating penile cancer. Infection with high-risk human papillomavirus (HPV) is associated with penile cancer and may be associated with an improved survival for those patients. The carcinogenesis that begins with HPV infection will be another area where therapies could be developed to target the specific HPV oncoproteins E5, E6 and E7.
This box summarizes key points contained in the article.
such as selective COX inhibitors (celecoxib) and traditional chemotherapeutics will likely further improve the survival of these patients. Chemotherapy The mainstay in advanced penile cancer is cisplatin-based combination chemotherapy. There have been a handful of clinical trials addressing these patients with response rates between 15 and 55% and median overall survival ranging between 5 and 12 months [7,8]. The combinations that have been studied include: bleomycin, methotrexate and cisplatin; cisplatin and 5-fluorouracil; cisplatin and irinotecan; and paclitaxel [9]. A balance between toxicity of therapy and efficacy is necessary, as many of the earlier agents that were utilized resulted in significant high-grade adverse events [10]. The utilization of newer targeted therapies can potentially result in improving outcomes in patients, while minimizing toxicity. 1.1
Neoadjuvant In patients with initially surgically unresectable disease (those with fixed, multiple, bulky > 4 cm nodes) the utilization of chemotherapy can allow for these tumors to become resectable resulting in improved survival. In a landmark Phase II clinical trial by Pagliaro et al., 30 patients with metastatic penile cancer received ifosfamide, paclitaxel and cisplatin. There was a 50% objective response in these patients, with 73% of patients ultimately undergoing surgery. Among those patients, 10% had evidence of a pathological complete response. Factors that were associated with worse survival were poor performance status and immobility of the groin mass as well as extranodal extension, skin involvement and bilateral residual tumor [11]. Future trials including the use 1.2
960
of novel targeted agents may demonstrate an even more impressive response taking patients who were previously unable to undergo surgery and making them surgical candidates and improving their survival [12]. 2.
Molecular markers and targets
E-Cadherin, MMP and Kirsten rat sarcoma With the advancement in techniques for molecular genomics, biomarkers that help relate important information about a patient’s disease are becoming increasingly a part of the clinician’s prediction tools [13]. While the presence of pathologically confirmed metastasis in a patient’s lymph nodes is still the most important factor regarding survival and disease-free interval, recent studies have shown similar associations among molecular markers that are known accomplices to tumor metastasis and recurrence [14]. Understanding how cancer cells are capable of gaining the ability to spread distantly is partly explained with a cell’s epithelial-to-mesenchymal transition (EMT) that is a hallmark of cancer [15]. This explains how the differential expression and repression of key factors in the cellular microenvironment lead to cell invasion and ultimately to metastasis. Many of the current and past studies on molecular markers stem from identification of these factors that are involved with the EMT. In a study by Campos et al., patients who had undergone both excision of their penile cancer and bilateral lymphadenectomy had their tissue stained for the presence of E-cadherin and MMP-2 and MMP-9. The significance of these markers has been demonstrated in other carcinomas with the author’s goal being to observe if they had any association with penile cancer metastasis or recurrence [16]. E-cadherin is responsible for maintaining cellular adhesion and signal transduction. Decreased expression of E-cadherin has been associated with cancer metastasis. In addition, MMPs are also involved with the EMT as they are enzymes that help degrade the basement membrane of a cell resulting in tumor metastasis. The results of the Campos et al. study demonstrated a significant association with low E-cadherin immunoreactivity and the presence of lymph node metastases (p = 0.03). In patients with high levels of MMP-9 immunoreactivity, there was a significant association on both univariate and multivariate analyses with disease recurrence (p = 0.02) [17]. These observations warrant further prospective evaluation and external validation in other larger populations. Although these are observations from a small cohort of patients, measuring the levels of MMP and E-cadherin in larger cohorts of patients and validating these data will be crucial to future incorporation of this information as a personalized approach to a patient’s treatment plan [18]. 2.1
Epidermal growth factor receptor The overexpression of the EGFR has been implicated in the poor prognosis of multiple carcinomas [19]. Chaux et al. recently performed immunohistochemical studies on the tissues of 112 patients with penile squamous cell carcinoma 2.2
Expert Opin. Drug Discov. (2014) 9(8)
Novel targeted therapies for the treatment of penile cancer
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Table 1. Anti-EGFR therapy in penile cancer. Study group
Number of patients
Prior chemotherapy
Necchi et al. (2011) [27]
10
All with ‡ 1 cycle
Panitumumab
Present
Brown et al. (2014) [29]
3
ITP
Cetuximab
Present
ITP and TPF
Panitumumab
Present
ITP
Cetuximab
Present
All with ‡ 1 cycle
Cetuximab (67%), erlotinib, gefitinib
13/13 positive
Carthon et al. (2013) [30]
24
Treatment drug
EGFR expression
Partial response 1 patient
Complete response 2 patients
Side effects 1 grade 3 -- 4 cutaneous toxicity, 1 diarrhea and 2 mucositis
42 months disease free Radiographic regression of tumor None 1/5 (cetuximab), 3/12 (cetuximab + cisplatin), 2/3 (cetuximab +TIP)
None None
Hemorrhage of tumor Grade 1 -- 2 skin rash (71%), 4 grade 3 -- 4 toxicities (bronchospasm, cellulitis, thrombocytopenia and hemorrhage)
TIP: Paclitaxel, Ifosfamide, Cisplatin; TPF: Docetaxel, Cisplatin, 5-Fluorouracil.
(SCC). They found EGFR expression to be prevalent in 88% of cases independent of histological subtype, grade and human papillomavirus (HPV) status [20]. EGFR, which has tyrosine kinase activity, is activated by the ligands EGF and TGF-a [21]. EGFR activation is known to cause a reduction in the expression of E-cadherin, which is a major factor in EMT. This reduction in E-cadherin is a result of the elevation in MMP-9 activity, which causes disruption in cellular adhesion [22]. Recently, Wang et al. demonstrated that a reduction in E-Cadherin results in overexpression of EGFR through experiments utilizing reverse transcriptase polymerase chain reaction (RT-PCR). They also performed in vitro studies utilizing the EGFR-specific tyrosine kinase inhibitor (erlotinib), blocking the effect of E-cadherin reduction on cell proliferation. These experiments were done in a SCC of the head and neck model, which along with SCC of the vulva behaves similarly as penile carcinoma in terms of response to therapy [23]. Zuo et al. similarly demonstrated the actions of EGFR and its involvement with tumor invasion due to an EMT-like change. In their study, by utilizing a SCC line from head and neck cancers, they demonstrated how activation of EGFR results in downregulation of E-cadherin along with increased production of MMP-9. They also observed that pharmacological inhibition of EGFR reduced production of MMP, thus, in turn reducing cell migration and invasion [24]. With the established antineoplastic in vitro effect that results with EGFR inhibition, there have also been clinical trials that show the efficacy and improvement in patient’s survival with medications that halt the activation of the EGFR [25]. In a randomized controlled clinical trial by
Burtness et al., patients with recurrent or metastatic SCC of the head and neck who received cisplatin combined with cetuximab (a mAb that binds the extracellular portion of EGFR) had an improved objective response rate (26%) compared to those who received cisplatin alone (10%). Cetuximab is given intravenously in weekly doses for the duration of therapy. An interesting observation, which the authors mention has been similarly seen in colorectal cancer patients, was the development of a characteristic skin rash in those patients receiving the EGFR inhibitor. In fact, the patient’s survival was found to be improved based on whether they developed the characteristic skin rash or not (hazard ratio [HR] of 0.42). In this trial, patients who had EGFR expression had an increased objective response to therapy with cetuximab (in those with low-to-moderate EGFR expression, the response was 40% compared to 11.5% for those who received placebo, p = 0.03) [26]. The effectiveness of anti-EGFR targeted therapy in penile cancer has been evaluated recently in a series of case reports and retrospective reviews (Table 1). In 2011, Necchi et al. described one of the first proofs of activity of EGFR blockade resulting in tumor regression in a patient with relapsed SCC of the penis. The patient they described had high-grade penile cancer and had undergone partial penectomy with bilateral inguinal and pelvic lymph node dissection with metastasis present in both inguinal and pelvic nodal specimens. The patient subsequently underwent treatment with docetaxel, cisplatin and 5-fluorouracil. Approximately 1 year later the patient presented with recurrent disease in the form of fixed and painful cutaneous nodules on both legs and scrotum consistent with SCC. The lesions were strongly positive for
Expert Opin. Drug Discov. (2014) 9(8)
961
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
G. Agarwal et al.
EGFR, and absent for Kirsten rat sarcoma (KRAS) mutations. The patient then started the anti-EGFR mAb panitumumab every 14 days. The patient experienced a significant response in the form of reduction in the size and number of cutaneous metastatic nodules and improvement in disease-related symptoms as well as normalization of the patient’s imaging [27]. The same group, Necchi et al., presented their results using panitumumab in a prospectively studied patient cohort between 10/2010 and 10/2012. They enrolled 10 patients, of which 9 of the patients had previously received 2 cycles of chemotherapy and 1 patient was chemo-naı¨ve. They reported five patients who had moderate EGFR expression that experienced response (two complete responses, one partial response and two patients with stable disease). These three patients had minimal side effects such as cutaneous toxicity, diarrhea and mucositis [28]. This series provides an example of the benefit with reduced major side effects achieved by EGFR blockade leaving another possible treatment for those patients who have recurrent or metastatic SCC of the penis refractory to combination chemotherapy regimens. Brown et al. recently described a set of three patients with penile cancer who were successfully treated with EGFR blockage. The first patient had received neoadjuvant chemotherapy followed by partial penectomy, right inguinal node dissection and bilateral pelvic node dissection with pathology revealing persistent metastatic disease. The patient had recurrent disease in his left groin and pelvis and was placed on cetuximab for 12 weekly doses. The patient experienced a near complete clinical and radiographical response after EGFR blockade. The patient had EGFR expression in his tissue at a low level and had absence of KRAS mutations. In the second patient who received EGFR blockade, there was progression while on therapy; this patient similarly had low levels of EGFR expression on immunohistochemistry. The third patient had treatment for refractory penile cancer with panitumumab and experienced partial response; however, the patient did develop recurrence after 2 months of treatment; this patient had moderate EGFR expression on tissue analysis. An interesting observation the authors of this study found was the difference in response to treatment between EGFR expression represented by immunohistochemistry and that by EGFR mRNA expression; however, given that this is a small case series, further larger studies will be needed to develop prediction tools to help select what patients would benefit most from therapy [29]. Another demonstration of the effect that EGFR targeted therapy has on penile cancer was made in a case series recently published by Carthon et al. In this group, 24 patients with advanced or metastatic penile cancer received EGFR-targeted therapy in the form of cetuximab, erlotinib or gefitinib (67% received cetuximab) following chemotherapy. Interestingly in this group, 3 out of 24 patients who received EGFR therapy after no response to conventional chemotherapy underwent consolidative surgery due to regression of their disease with combination of EGFR targeted therapy and chemotherapy. 962
Those three patients demonstrated improved overall survival compared to those who did not undergo consolidative surgery and two of the patients experienced long-term disease-free survival. In this retrospective cohort tissue, one limitation was that staining for EGFR was only performed in 13 of the 24 patients; although all 13 had EGFR positivity, no stratification based on degree of EGFR staining was described. Another observation from this study was the decrease in overall survival in patients with visceral or bone metastasis despite response to therapy [30]. A part of the EGFR signaling cascade, the KRAS gene has been studied with respect to sensitivity to anti-EGFR therapy [31]. Gou et al. took the tissue from 150 patients with penile SCC and identified overexpression of EGFR in 92% of those patients, while also finding only one patient with KRAS gene mutation [32]. This is important as it has been demonstrated in patients with colorectal cancer that KRAS gene mutation is associated with insensitivity to antiEGFR therapy [33]. The importance of developing biomarkers which will help stratify patients into groups that will benefit the most or least from therapy is essential and must be done in parallel to the discovery of novel targeted therapeutic agents [34]. The very low incidence of penile cancer results in the demonstrated paucity of literature and small number of patients described in case series and reviews to date. In order to better understand which patients may benefit from targeted therapies, larger multi-institutional and collaborative studies will need to be performed. COX-2 and prostaglandin E synthase 1 The anti-inflammatory group of medications, which includes aspirin, has been available for many years. Through the mass utilization of these medications by the general population, trends in the reduction of certain cancers have been observed, which have led efforts by scientists to understand the mechanism of action for this antineoplastic effect. The COX enzymes, also known as prostaglandin endoperoxide synthases, convert arachidonic acid into prostaglandins, which can be further converted, and produce the actions we are familiar with such as inflammation, platelet aggregation, bone resorption and maintenance of gastric and renal blood flow. There have been three isoforms of COX identified of which COX-1 and COX-2 are the best studied. COX-1 is expressed constitutively throughout the body, whereas COX-2 is an inducible enzyme mainly by hypoxia and tissue injury [35]. The pathway of COX inhibition occurs via two routes: the nonselective inhibition as seen with aspirin and ibuprofen which blocks both COX-1 and COX-2 and the selective inhibition through blockade of COX-2, utilizing drugs such as celecoxib. The analgesic effect of COX is mediated through COX-2, whereas the other vascular and gastrointestinal effects are mediated by COX-1. Thus, selective inhibition of COX-2 has been utilized in rheumatoid and osteoarthritis to allow for the beneficial effect of pain relief with a reduction in the side 2.3
Expert Opin. Drug Discov. (2014) 9(8)
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Novel targeted therapies for the treatment of penile cancer
effects such as gastroduodenal ulcers, impaired renal blood flow and increased risk of bleeding due to the reduction in platelet aggregation. In a meta-analysis of all of the clinical trials involving COX-2 inhibition, there was an increased risk of myocardial infarction seen with chronic use of COX-2 inhibitors. However, this risk is similar to that caused by other nonsteroidal anti-inflammatories such as ibuprofen when used long term [36]. The antineoplastic effect of COX inhibition has been found to be mediated primarily by blockade of COX-2. COX-2 is activated in response to tissue injury and results in a proinflammatory response. The cascade of events following activation of COX-2 causes recruitment of factors involved with angiogenesis such as VEGF. In addition to the resultant neovascularity, there is a decrease in apoptosis, an increase in cellular motility and decrease in the patients’ natural immune response to tumorigenesis [37]. There is an increased expression of COX-2 in a number of tumor types; however, it has been most studied in colorectal cancers. The activity of COX-2 inhibition has also been demonstrated in this tumor subtype. Recently, Shin et al. demonstrated the efficacy of combined EGFR and COX-2 inhibition in a head and neck SCC cell line. The combination therapy resulted in reduced progression compared to either agent alone. In a Phase I trial of chemoprevention with EGFR and COX-2 inhibition, Shin et al. showed a pathological response rate of 71% in patients with premalignant lesions that were treated with the dual therapy for chemoprevention [38]. Golijanin et al. determined tissue expression of COX-2 in penile carcinoma in situ, invasive SCC and metastatic SCC to the lymph nodes. They were able to confirm that there is an overexpression of COX-2 in all these penile carcinoma stages [39]. Utilizing this information and extrapolating from head and neck cancers as well as observations in gastrointestinal malignancies gives the basis for further studies of treating penile carcinoma with COX-2 inhibition. However, as is true for the other therapies mentioned, these will have to be validated prospectively and in randomized controlled trials to determine the true efficacy.
Tyrosine kinase inhibitors (sorafenib and sunitinib)
2.4
By utilizing combinations of targeted drug therapies, resistance mechanisms of tumors can be thwarted, resulting in improved survival for patients [40]. In this spirit, the application of wellstudied tyrosine kinase inhibitors, such as sorafenib and sunitinib as utilized in metastatic renal cell carcinoma, in patients with penile cancer is warranted [41]. To date, there is minimal prospective clinical trial evidence available; however, a small case series was published by Zhu et al. who described six patients with advanced penile cancer. In their series, all the patients had received two prior chemotherapy regimens and subsequently received either sunitinib or sorafenib. Of the six patients, one achieved a partial response and four had stable
disease. Serum SCC antigen as well as tissue microvessel density and Ki-67 levels were measured before and after therapy. In the patient who had a partial response, the serum SCC antigen level had a 95% reduction. In the other patients there was a reduction in microvessel density and Ki-67 levels [42]. This study by Zhu et al. combining treatment with diagnostics specific to penile cancer allows for direct observations of activity to be seen. This goes along with the concept of having molecular determinants of treatment efficacy aiding in selection of patients in the future who would benefit from therapy. Human papillomavirus There is an association between high risk HPV types and anogenital carcinomas. In penile cancer, the predominant HPV subtypes are 16 and 18 and these are found in 40% of patients [43]. These higher risk HPV types encode three oncogenic proteins, namely E5, E6, and E7. The E5 protein has been associated with activation of EGFR in addition to other receptor tyrosine kinases. The E7 proteins degrade the retinoblastoma tumor suppressor. This along with the E6 proteins targeting of the p53 tumor suppressor results in cell proliferation. In addition, these oncoproteins result in increased angiogenesis and other processes involved with the EMT that is associated with invasive and metastatic carcinoma [44]. Based on the findings that HPV infection is associated with both premalignant and malignant cervical cancer, a vaccine against HPV has been developed and thus far has been shown to be effective in up to 99% of patients [45]. These positive results in randomized trials have led to the FDA approval of the vaccine which is indicated for females aged 9 -- 26 for the prevention of cervical, vulvar and vaginal cancers, and for males and females aged 9 -- 26 for the prevention of anal cancer, precancerous or dysplastic lesions and genital warts caused by HPV types 6,11, 16 and 18 [46,47]. In addition to the vaccination, there have been efforts to target the specific actions of the HPV oncoproteins (E6 and E7) and their pathways. Thus far there have been few promising studies that have shown efficacy with this type of approach; however, ongoing research projects investigating the different pathways to alter this mechanism of oncogenesis are in progress [44]. The role of HPV as a determinant of prognosis in penile cancer patients is unclear [48]. In patients with head and neck carcinoma, survival rates were improved in those who were found to have tissue with the presence of HPV [49]. In a case series of 82 patients with penile cancer, men with HPVpositive tumors had a non-statistically significant decreased rate of metastasis compared to those without HPV [50]. A study by Lont et al. looked at 171 patients with penile cancer and tested their tissue for high-risk HPV. They found that 29% of the tumors were positive for high-risk HPV, and there was a significant difference in 5-year disease-specific survival with a reduction in risk of dying from disease (HR = 0.14, p=0.01) in those patients who were positive for high-risk HPV [51]. The findings in these small retrospective studies 2.5
Expert Opin. Drug Discov. (2014) 9(8)
963
G. Agarwal et al.
EGF
PGE2
Arachidonic COX-2 Acid
EGFR
PI3K
HIF1 alpha
MMP
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Cell migration and invasion
Survivin
VEGF Degradation
Decreased apoptosis angiogenesis
E-cadherin
Figure 1. Schematic representation of the signaling pathway for EGF and prostaglandins responsible for neoplasia. HIF1-a: Hypoxia-inducible factor 1-a; PGE2: Prostaglandin E2; PI3K: Phosphoinositide 3-kinase.
warrant further prospective multi-institutional collaborations in order to better understand not only the association between high-risk HPV infection and improved survival but also the mechanistic process causing this [52]. An understanding of the pathway of events involved allows for the development of targeted therapies [53].
Lymphangiogenesis and the mammalian target of rapamycin
2.6
The lymph node status of patients with invasive penile SCC is crucial in determining a patient’s treatment plan and plays a major role in the clinician’s assessment of a patient’s prognosis. Understanding the molecular mechanisms responsible for lymph node metastasis would possibly allow for a better assessment of which patients may display more aggressive disease than others. Understanding lymphangiogenesis would also leave this as another avenue for targeted therapy [54]. This will also aid in selection of which patients would benefit from an upfront lymph node dissection versus a delayed approach. Some investigators believe that existing peritumoral lymph vessels do not play a major role in the development of metastasis [55], whereas others believe intratumoral lymphangiogenesis has a significant association with nodal metastasis [56], Naumann et al. did not find an association between lymph vessel density at peritumoral or intratumoral sites and the presence of lymph node metastasis in patients with penile SCC [55]. However, what they found as the major driver of lymph node metastasis was the presence of lymphovascular invasion. This is contrary to findings in the head and neck carcinoma literature where the development of intratumoral lymphatics was found to be highly associated with both metastasis and prognosis in those patients [56]. Investigation of other targets for therapy to prevent or treat lymph node metastasis in penile cancer led to the evaluation of mammalian target of rapamycin (mTOR) expression in the 964
tissue of these patients. Ferrandiz-Pulido et al. performed immunohistochemical staining on the tissue of 67 patients with invasive penile cancer. They found an overexpression of phosphorylated mTOR in those patients with lymph node disease [57]. Chaux et al. similarly looked at 112 cases of patients with penile carcinoma evaluating the expression of markers along the mTOR pathway (phosphatase and tension homolog, phosphorylated AKT and phosphorylated mTOR) [58]. They found aberrant expression of these markers, indicating a role for further study of the mTOR pathway in penile cancer. Although mTOR inhibition has not been studied for the treatment of penile SCC, corollaries from the head and neck literature make this targeted treatment a worthwhile agent to study further. Ekshyyan et al. used a mouse model of SCC of the head and neck to study the anti-lymphangiogenesis effects of mTOR inhibition in vivo. They found that rapamycin (an mTOR inhibitor) significantly decreased lymphatic vessel density and decreased lymph node metastasis [59]. Patel et al. used a mouse model for head and neck SCC to further characterize the association between mTOR pathways and metastatic disease as well as the role of mTOR inhibition for treatment of the disease. They found that mice that had tumor spread to their lymph nodes had elevated mTOR activity and that inhibition with rapamycin decreased lymphangiogenesis in the primary tumors and prevented metastatic spread of disease, thus improving survival [60]. Future studies should incorporate the study of lymphangiogenesis in penile cancer and the expression of mTOR in tissue of these patients to further characterize the role of such markers in the prognosis and response to treatment. 3.
Expert opinion
Penile cancer, although rare in the USA, is a uniformly lethal disease when it presents in the advanced stages. With a greater
Expert Opin. Drug Discov. (2014) 9(8)
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Novel targeted therapies for the treatment of penile cancer
understanding of tumor biology and the human body’s innate defense mechanisms to prevent neoplasia, the advent of targeted therapy has entered a rapidly evolving era of study (Figure 1). The balance between toxicity of treatment and efficacy will also continue to improve as the agents become more specific. Of paramount importance is the discovery of biomarkers alongside the targeted therapies so that when performing clinical trials these markers can be correlated with efficacy and response to therapy. This will allow future patients to be selected for treatment with specific agents based on their tumor histology and molecular signature. An understanding of the process by which a normal cell undergoes malignant transformation in patients who develop penile cancer can be gained when studying the interactions between high-risk HPV and tissue from the patients afflicted with the disease. In fact, the research involved with HPV and its association with premalignant and malignant lesions led to the introduction of an HPV vaccine which, by 2040, will result in the virtual elimination of cervical cancer in the USA [44]. Targeted therapies should be developed at every stage where intervention is possible in a patient’s life. This includes behavior and lifestyle modifications, an understanding of risk factors and development of vaccines for prevention of disease. The next stage would be to develop biomarkers for improved detection and stratification of patients who harbor aggressive disease. After patients are stratified, an improvement and more specific targeted treatment of disease in a neoadjuvant and adjuvant settings should be sought after. Currently, the magnitude of advancement is at a staggering pace and with continued efforts our patients will see an improvement in their survival. Some of the most promising therapies are those that target the EGFR. These agents have been utilized in a small series of patients; however, extrapolating from randomized clinical trial evidence in the head and neck SCC literature as well as small case series demonstrating partial and some complete responses, this therapy warrants multi-institutional validation studies. In addition, the role of
COX-2 inhibition in the chemoprevention and treatment of penile carcinoma deserves continued attention. Moreover, targeting the mTOR pathway in patients with invasive penile cancer may have not only a primary role but also an additive effect with other therapies. Ultimately, a combination of chemotherapy and targeted agents will be adopted, starting with those with advanced tumors, and ultimately it would be utilized in the neoadjuvant setting. A better understanding of the molecular pathways involved with tumorigenesis in penile cancer as well as an understanding of metastatic spread of disease concurrent with immunohistochemical analysis to identify markers of disease alongside clinical trials that treat patients with targeted agents needs to occur before widespread adoption of these novel therapies. For instance, EGFR expression is present in almost all patients with penile cancer; thus, further analysis of the degree of expression as a marker of treatment efficacy needs to occur as in its current state; this may not be a good marker for selecting patients or even evaluating response to therapy. Within the next decade, a personalized approach to treat patients with invasive penile carcinoma will occur. Determining which patients should be observed after primary treatment of a penile tumor and who should go on to lymphadenectomy can be aided by developing reliable markers of disease aggressiveness. The patient-tailored approach using molecular markers will allow for not only decreased morbidity by avoiding overtreatment but also improved survival by selecting patients who are most likely to benefit from additional therapy.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
Expert Opin. Drug Discov. (2014) 9(8)
965
G. Agarwal et al.
Bibliography
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29
2.
Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol 2010;57(6):1002-12
3.
Kacker S, Frick KD, Gaydos CA, et al. Costs and effectiveness of neonatal male circumcision. Arch Pediatr Adolesc Med 2012;166(10):910-18
4.
Burt LM, Shrieve DC, Tward JD. Stage presentation, care patterns, and treatment outcomes for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 2014;88(1):94-100
5.
Moses KA, Winer A, Sfakianos JP, et al. Contemporary management of penile cancer: greater than 15 year MSKCC experience. Can J Urol 2014;21(2):7201-6
6.
Spiess PE; National Comprehensive Cancer Network. New treatment guidelines for penile cancer. J Natl Compr Canc Netw 2013;11(Suppl 5):659-62
7.
Protzel C, Seitz AK, Hakenberg OW, et al. [Neoadjuvant, adjuvant and palliative chemotherapy of penile cancer]. Urologe A 2013;52(11):1556-60.62-3
8.
Zanetta G, Lissoni A, Pellegrino A, et al. Neoadjuvant chemotherapy with cisplatin, ifosfamide and paclitaxel for locally advanced squamous-cell cervical cancer. Ann Oncol 1998;9(9):977-80
9.
..
10.
11.
966
Sonpavde G, Pagliaro LC, Buonerba C, et al. Penile cancer: current therapy and future directions. Ann Oncol 2013;24(5):1179-89 This article provides a nice summary of recent literature regarding the treatment of advanced penile cancer. Nicholson S, Hall E, Harland SJ, et al. Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/ 001). Br J Cancer 2013;109(10):2554-9 Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic
..
penile cancer: a phase II study. J Clin Oncol 2010;28(24):3851-7 This is a landmark article detailing a very important clinical trial utilizing neoadjuvant chemotherapy for penile cancer.
12.
Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Cancer Netw 2013;11(5):617-24
13.
Pietrantonio F, Biondani P, Verzoni E, et al. Management of advanced genitourinary tumors. Tumori 2012;98(2):264-6
14.
Gunia S, Erbersdobler A, Hakenberg OW, et al. C-MET is expressed in the majority of penile squamous cell carcinomas and correlates with polysomy-7 but is not associated with MET oncogene amplification, pertinent histopathologic parameters, or with cancer-specific survival. Pathol Res Pract 2013;209(4):215-20
15.
.
16.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74 This article is an essential read for any reader interested in having a better understanding of carcinogenesis. Umbas R, Schalken JA, Aalders TW, et al. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 1992;52(18):5104-9
17.
Campos RS, Lopes A, Guimaraes GC, et al. E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology 2006;67(4):797-802
18.
Nelson R. Potential prognostic markers in penile cancer. Lancet Oncol 2006;7(5):369
19.
20.
Pedersen MW, Meltorn M, Damstrup L, et al. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol 2001;12(6):745-60 Chaux A, Cohen JS, Schultz L, et al. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded
Expert Opin. Drug Discov. (2014) 9(8)
archival tissues. Hum Pathol 2012;43(10):1590-5 21.
Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366(1):2-16
22.
Haley JD, Gullick WJ. EGFR signaling networks in cancer therapy. Humana Press, New York, NY; 2008. p. 221-35 This is a detailed book that goes through EGFR from start to finish regarding discovery of current ways to target it in multiple solid organ malignancies.
.
23.
Wang D, Su L, Huang D, et al. Downregulation of E-Cadherin enhances proliferation of head and neck cancer through transcriptional regulation of EGFR. Mol Cancer 2011;10:116
24.
Zuo JH, Zhu W, Li MY, et al. Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin. J Cell Biochem 2011;112(9):2508-17
25.
Baker CH, Kedar D, McCarty MF, et al. Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J pathol 2002;161(3):929-38
26.
Burtness B, Goldwasser MA, Flood W, et al. Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/ recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23(34):8646-54
27.
Necchi A, Nicolai N, Colecchia M, et al. Proof of activity of anti-epidermal growth factor receptor-targeted therapy for relapsed squamous cell carcinoma of the penis. J Clin Oncol 2011;29(22):e650-2 This is one of the first descriptions of efficacy of anti-EGFR therapy in penile cancer.
.
28.
Giannatempo P. Early results of the pilot study with the anti-epidermal growthfactor receptor (EGFR) monoclonal antibody panitumumab in patients (PTS) with multi-relapsed or refractory
Novel targeted therapies for the treatment of penile cancer
29.
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
30.
Brown A, Ma Y, Danenberg K, et al. Epidermal growth factor receptortargeted therapy in squamous cell carcinoma of the penis: a report of 3 cases. Urology 2014;83(1):159-65 Carthon BC, Ng CS, Pettaway CA, et al. Epidermal growth factor receptortargeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int 2013
31.
Plesec TP, Hunt JL. KRAS mutation testing in colorectal cancer. Adv Anat Pathol 2009;16(4):196-203
32.
Gou HF, Li X, Qiu M, et al. Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma. PLoS One 2013;8(4):e62175 This is a nice article highlighting the EGFR pathway.
.
33.
34.
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360(14):1408-17 Carlson BC, Hofer MD, Ballek N, et al. Protein markers of malignant potential in penile and vulvar lichen sclerosus. J Urol 2013;190(2):399-406
35.
Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004;56(3):387-437
36.
Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086
37.
..
38.
39.
Pruthi RS, Derksen E, Gaston K. Cyclooxygenase-2 as a potential target in the prevention and treatment of genitourinary tumors: a review. J Urol 2003;169(6):2352-9 This is a very nice review of COX-2 and its role in multiple urologic cancers. Shin DM, Zhang H, Saba NF, et al. Chemoprevention of head and neck cancer by simultaneous blocking of epidermal growth factor receptor and cyclooxygenase-2 signaling pathways: preclinical and clinical studies. Clin Cancer Res 2013;19(5):1244-56 Golijanin D, Tan JY, Kazior A, et al. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are
of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 2001;91(12):2315-21
overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res 2004;10(3):1024-31
squamous cell Carcinoma (SCC) of the Penis. J Urol 2013;189(No. 4S):e309 40.
Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology 2009;76(5):350-4
51.
Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006;119(5):1078-81
41.
Mooney D, Paluri R, Mehta A, et al. Update in systemic therapy of urologic malignancies. Postgrad Med 2014;126(1):44-54
52.
42.
Zhu Y, Li H, Yao XD, et al. Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: a preliminary report. Urol Int 2010;85(3):334-40
Fonseca AG, Soares FA, Burbano RR, et al. Human papilloma Virus: prevalence, distribution and predictive value to lymphatic metastasis in penile carcinoma. Int Braz J Urol 2013;39(4):542-50
53.
Connolly K, Manders P, Earls P, et al. Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control. Cancer Treat Rev 2014;40(2):205-14
54.
Karpanen T, Alitalo K. Lymphatic vessels as targets of tumor therapy? J Exp Med 2001;194(6):F37-42
55.
Naumann CM, Al-Najar A, Alkatout I, et al. Lymphatic spread in squamous cell carcinoma of the penis is independent of elevated lymph vessel density. BJU Int 2009;103(12):1655-9.discussion 59
56.
Maula SM, Luukkaa M, Grenman R, et al. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 2003;63(8):1920-6
57.
Ferrandiz-Pulido C, Masferrer E, Toll A, et al. mTOR signaling pathway in penile squamous cell carcinoma: pmTOR and peIF4E over expression correlate with aggressive tumor behavior. J Urol 2013;190(6):2288-95
58.
Chaux A, Munari E, Cubilla AL, et al. Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases. Histopathology 2014;64(6):863-71
59.
Ekshyyan O, Moore-Medlin TN, Raley MC, et al. Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models. BMC Cancer 2013;13:320
60.
Patel V, Marsh CA, Dorsam RT, et al. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Res 2011;71(22):7103-12
43.
.
Flaherty A, Kim T, Giuliano A, et al. Implications for human papilloma virus in penile cancer. Urol Oncol 2014;32(1):53 e1-8 This is a nice review of the role that human papillomavirus has in penile cancer.
44.
Hellner K, Munger K. Human papillomaviruses as therapeutic targets in human cancer. J Clin Oncol 2011;29(13):1785-94
45.
Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a doubleblind, randomised study in young women. Lancet 2009;374(9686):301-14
46.
Merck & Co. I. Highlights of prescribing information for gardisil. product information packet 2011
47.
de Bruijn RE, Heideman DA, Kenter GG, et al. Patients with penile cancer and the risk of (pre)malignant cervical lesions in female partners: a retrospective cohort analysis. BJU int 2013;112(7):905-8
48.
49.
50.
Zhai JP, Wang QY, Wei D, et al. [Association between HPV DNA and disease specific survival in patients with penile cancer]. Zhonghua Yi Xue Za Zhi 2013;93(34):2719-22 O’Rorke MA, Ellison MV, Murray LJ, et al. Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 2012;48(12):1191-201 Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis
Expert Opin. Drug Discov. (2014) 9(8)
967
G. Agarwal et al.
Affiliation
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Gautum Agarwal1 MD, Shilpa Gupta1 MD & Philippe E Spiess†2 MD MS FACS † Author for correspondence 1 Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, FL, USA 2 Associate member, Moffitt Cancer Center, Department of Genitourinary Oncology, 12902 Magnolia Drive office 12538, Tampa, FL 33612, USA Tel: +1 813 745 8343; Fax: +1 813 745 8494; E-mail: [email protected]
968
Expert Opin. Drug Discov. (2014) 9(8)
Expert Opinion on Drug Discovery Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/iedc20
Novel targeted therapies for the treatment of penile cancer a
a
b
Gautum Agarwal MD , Shilpa Gupta MD & Philippe E Spiess MD MS FACS Associate member a
Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, FL, USA
b
Moffitt Cancer Center, Department of Genitourinary Oncology, 12902 Magnolia Drive office 12538, Tampa, FL 33612, USA +1 813 745 8343; +1 813 745 8494; Published online: 04 Jun 2014.
Click for updates To cite this article: Gautum Agarwal MD, Shilpa Gupta MD & Philippe E Spiess MD MS FACS Associate member (2014) Novel targeted therapies for the treatment of penile cancer, Expert Opinion on Drug Discovery, 9:8, 959-968 To link to this article: http://dx.doi.org/10.1517/17460441.2014.925875
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Review
Novel targeted therapies for the treatment of penile cancer
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Gautum Agarwal, Shilpa Gupta & Philippe E Spiess† Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, FL, USA
1.
Introduction
2.
Molecular markers and targets
3.
Expert opinion
Introduction: The treatment of penile cancer has changed over the past decade in that it was primarily a surgically managed disease and those with locally advanced or metastatic disease uniformly had a very poor prognosis. However, with the use of better traditional systemic chemotherapeutic agents in the neoadjuvant and adjuvant settings, the disease-specific survival and general outlook has improved. However, there is still a large group of patients who will progress even while on systemic therapy. It is in those patients where the application of targeted therapies has been investigated with some experiencing partial or even complete responses. With the improvement seen in patients with chemotherapy refractory disease, the application of novel targeted agents in the neoadjuvant setting may have a resultant positive impact on patient survival. Areas covered: This review includes research pertaining to targeted therapies, biomarkers and signaling pathways involved with penile cancer. The article was based on a literature search using the keywords ‘penile cancer’ and ‘targeted therapies’. Expert opinion: Penile cancer at the advanced stages of the disease has a high mortality. The utilization of novel targeted therapies in these situations is warranted in combination with, or sequentially with, traditional cytotoxic chemotherapy to improve the patient survival rate. Personalized therapy is nearly here for penile cancer and should be made real within the next decade. Keywords: biomarkers, human papillomavirus, penile cancer, targeted therapy Expert Opin. Drug Discov. (2014) 9(8):959-968
1.
Introduction
In the USA, there will be ~ 1640 new cases of penile cancer diagnosed in 2014 and 320 patients will die from this disease [1]. Compared to other cancers, there is a very low incidence of penile cancer in the USA, < 1 per 100,000 males [2], due in part to the high prevalence of males who undergo neonatal circumcision (~ 55%) and improved penile hygiene [3]. Among those patients who develop penile cancer, ~ 20% will have metastatic disease on presentation, with distant metastasis present in 2.5% of patients [4]. Survival for someone with penile cancer is almost entirely dependent on the presence or absence of metastasis in the regional lymph nodes [5]. In the case of patients with palpable mobile inguinal lymph nodes that are < 4 cm, surgical excision is considered the standard of care and does provide some patients with cure. When the patient’s inguinal lymph nodes are fixed, > 4 cm, or there is involvement of pelvic lymph nodes with metastatic cancer, achievement of cure becomes near impossible; however, with the implementation of multimodal treatment involving systemic chemotherapy, surgery and radiation, there have been published series observing patients with a reliable treatment response [6]. With the advent of novel targeted therapeutic agents, patients who have failed to respond to traditional chemotherapeutic agents may have a response. Additional studies on the combination of these targeted agents with other antineoplastic drugs 10.1517/17460441.2014.925875 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted
959
G. Agarwal et al.
Article highlights. . .
.
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
.
.
EGFR is overexpressed in the majority of penile cancers, making this an excellent target for therapeutic benefit. The epithelial-to-mesenchymal transition explains the mechanisms of action involved with penile cancer tumor invasion, laying out potential targets for therapy. The activity of anti-EGFR agents is decreased when a patient expresses KRAS mutation, making this an important biomarker in selecting patients for therapy. COX-2 inhibition may play a role in the chemoprevention and treatment of penile cancer. The combination of COX-2 inhibition with other targeted therapies demonstrates a promising approach in treating penile cancer. Infection with high-risk human papillomavirus (HPV) is associated with penile cancer and may be associated with an improved survival for those patients. The carcinogenesis that begins with HPV infection will be another area where therapies could be developed to target the specific HPV oncoproteins E5, E6 and E7.
This box summarizes key points contained in the article.
such as selective COX inhibitors (celecoxib) and traditional chemotherapeutics will likely further improve the survival of these patients. Chemotherapy The mainstay in advanced penile cancer is cisplatin-based combination chemotherapy. There have been a handful of clinical trials addressing these patients with response rates between 15 and 55% and median overall survival ranging between 5 and 12 months [7,8]. The combinations that have been studied include: bleomycin, methotrexate and cisplatin; cisplatin and 5-fluorouracil; cisplatin and irinotecan; and paclitaxel [9]. A balance between toxicity of therapy and efficacy is necessary, as many of the earlier agents that were utilized resulted in significant high-grade adverse events [10]. The utilization of newer targeted therapies can potentially result in improving outcomes in patients, while minimizing toxicity. 1.1
Neoadjuvant In patients with initially surgically unresectable disease (those with fixed, multiple, bulky > 4 cm nodes) the utilization of chemotherapy can allow for these tumors to become resectable resulting in improved survival. In a landmark Phase II clinical trial by Pagliaro et al., 30 patients with metastatic penile cancer received ifosfamide, paclitaxel and cisplatin. There was a 50% objective response in these patients, with 73% of patients ultimately undergoing surgery. Among those patients, 10% had evidence of a pathological complete response. Factors that were associated with worse survival were poor performance status and immobility of the groin mass as well as extranodal extension, skin involvement and bilateral residual tumor [11]. Future trials including the use 1.2
960
of novel targeted agents may demonstrate an even more impressive response taking patients who were previously unable to undergo surgery and making them surgical candidates and improving their survival [12]. 2.
Molecular markers and targets
E-Cadherin, MMP and Kirsten rat sarcoma With the advancement in techniques for molecular genomics, biomarkers that help relate important information about a patient’s disease are becoming increasingly a part of the clinician’s prediction tools [13]. While the presence of pathologically confirmed metastasis in a patient’s lymph nodes is still the most important factor regarding survival and disease-free interval, recent studies have shown similar associations among molecular markers that are known accomplices to tumor metastasis and recurrence [14]. Understanding how cancer cells are capable of gaining the ability to spread distantly is partly explained with a cell’s epithelial-to-mesenchymal transition (EMT) that is a hallmark of cancer [15]. This explains how the differential expression and repression of key factors in the cellular microenvironment lead to cell invasion and ultimately to metastasis. Many of the current and past studies on molecular markers stem from identification of these factors that are involved with the EMT. In a study by Campos et al., patients who had undergone both excision of their penile cancer and bilateral lymphadenectomy had their tissue stained for the presence of E-cadherin and MMP-2 and MMP-9. The significance of these markers has been demonstrated in other carcinomas with the author’s goal being to observe if they had any association with penile cancer metastasis or recurrence [16]. E-cadherin is responsible for maintaining cellular adhesion and signal transduction. Decreased expression of E-cadherin has been associated with cancer metastasis. In addition, MMPs are also involved with the EMT as they are enzymes that help degrade the basement membrane of a cell resulting in tumor metastasis. The results of the Campos et al. study demonstrated a significant association with low E-cadherin immunoreactivity and the presence of lymph node metastases (p = 0.03). In patients with high levels of MMP-9 immunoreactivity, there was a significant association on both univariate and multivariate analyses with disease recurrence (p = 0.02) [17]. These observations warrant further prospective evaluation and external validation in other larger populations. Although these are observations from a small cohort of patients, measuring the levels of MMP and E-cadherin in larger cohorts of patients and validating these data will be crucial to future incorporation of this information as a personalized approach to a patient’s treatment plan [18]. 2.1
Epidermal growth factor receptor The overexpression of the EGFR has been implicated in the poor prognosis of multiple carcinomas [19]. Chaux et al. recently performed immunohistochemical studies on the tissues of 112 patients with penile squamous cell carcinoma 2.2
Expert Opin. Drug Discov. (2014) 9(8)
Novel targeted therapies for the treatment of penile cancer
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Table 1. Anti-EGFR therapy in penile cancer. Study group
Number of patients
Prior chemotherapy
Necchi et al. (2011) [27]
10
All with ‡ 1 cycle
Panitumumab
Present
Brown et al. (2014) [29]
3
ITP
Cetuximab
Present
ITP and TPF
Panitumumab
Present
ITP
Cetuximab
Present
All with ‡ 1 cycle
Cetuximab (67%), erlotinib, gefitinib
13/13 positive
Carthon et al. (2013) [30]
24
Treatment drug
EGFR expression
Partial response 1 patient
Complete response 2 patients
Side effects 1 grade 3 -- 4 cutaneous toxicity, 1 diarrhea and 2 mucositis
42 months disease free Radiographic regression of tumor None 1/5 (cetuximab), 3/12 (cetuximab + cisplatin), 2/3 (cetuximab +TIP)
None None
Hemorrhage of tumor Grade 1 -- 2 skin rash (71%), 4 grade 3 -- 4 toxicities (bronchospasm, cellulitis, thrombocytopenia and hemorrhage)
TIP: Paclitaxel, Ifosfamide, Cisplatin; TPF: Docetaxel, Cisplatin, 5-Fluorouracil.
(SCC). They found EGFR expression to be prevalent in 88% of cases independent of histological subtype, grade and human papillomavirus (HPV) status [20]. EGFR, which has tyrosine kinase activity, is activated by the ligands EGF and TGF-a [21]. EGFR activation is known to cause a reduction in the expression of E-cadherin, which is a major factor in EMT. This reduction in E-cadherin is a result of the elevation in MMP-9 activity, which causes disruption in cellular adhesion [22]. Recently, Wang et al. demonstrated that a reduction in E-Cadherin results in overexpression of EGFR through experiments utilizing reverse transcriptase polymerase chain reaction (RT-PCR). They also performed in vitro studies utilizing the EGFR-specific tyrosine kinase inhibitor (erlotinib), blocking the effect of E-cadherin reduction on cell proliferation. These experiments were done in a SCC of the head and neck model, which along with SCC of the vulva behaves similarly as penile carcinoma in terms of response to therapy [23]. Zuo et al. similarly demonstrated the actions of EGFR and its involvement with tumor invasion due to an EMT-like change. In their study, by utilizing a SCC line from head and neck cancers, they demonstrated how activation of EGFR results in downregulation of E-cadherin along with increased production of MMP-9. They also observed that pharmacological inhibition of EGFR reduced production of MMP, thus, in turn reducing cell migration and invasion [24]. With the established antineoplastic in vitro effect that results with EGFR inhibition, there have also been clinical trials that show the efficacy and improvement in patient’s survival with medications that halt the activation of the EGFR [25]. In a randomized controlled clinical trial by
Burtness et al., patients with recurrent or metastatic SCC of the head and neck who received cisplatin combined with cetuximab (a mAb that binds the extracellular portion of EGFR) had an improved objective response rate (26%) compared to those who received cisplatin alone (10%). Cetuximab is given intravenously in weekly doses for the duration of therapy. An interesting observation, which the authors mention has been similarly seen in colorectal cancer patients, was the development of a characteristic skin rash in those patients receiving the EGFR inhibitor. In fact, the patient’s survival was found to be improved based on whether they developed the characteristic skin rash or not (hazard ratio [HR] of 0.42). In this trial, patients who had EGFR expression had an increased objective response to therapy with cetuximab (in those with low-to-moderate EGFR expression, the response was 40% compared to 11.5% for those who received placebo, p = 0.03) [26]. The effectiveness of anti-EGFR targeted therapy in penile cancer has been evaluated recently in a series of case reports and retrospective reviews (Table 1). In 2011, Necchi et al. described one of the first proofs of activity of EGFR blockade resulting in tumor regression in a patient with relapsed SCC of the penis. The patient they described had high-grade penile cancer and had undergone partial penectomy with bilateral inguinal and pelvic lymph node dissection with metastasis present in both inguinal and pelvic nodal specimens. The patient subsequently underwent treatment with docetaxel, cisplatin and 5-fluorouracil. Approximately 1 year later the patient presented with recurrent disease in the form of fixed and painful cutaneous nodules on both legs and scrotum consistent with SCC. The lesions were strongly positive for
Expert Opin. Drug Discov. (2014) 9(8)
961
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
G. Agarwal et al.
EGFR, and absent for Kirsten rat sarcoma (KRAS) mutations. The patient then started the anti-EGFR mAb panitumumab every 14 days. The patient experienced a significant response in the form of reduction in the size and number of cutaneous metastatic nodules and improvement in disease-related symptoms as well as normalization of the patient’s imaging [27]. The same group, Necchi et al., presented their results using panitumumab in a prospectively studied patient cohort between 10/2010 and 10/2012. They enrolled 10 patients, of which 9 of the patients had previously received 2 cycles of chemotherapy and 1 patient was chemo-naı¨ve. They reported five patients who had moderate EGFR expression that experienced response (two complete responses, one partial response and two patients with stable disease). These three patients had minimal side effects such as cutaneous toxicity, diarrhea and mucositis [28]. This series provides an example of the benefit with reduced major side effects achieved by EGFR blockade leaving another possible treatment for those patients who have recurrent or metastatic SCC of the penis refractory to combination chemotherapy regimens. Brown et al. recently described a set of three patients with penile cancer who were successfully treated with EGFR blockage. The first patient had received neoadjuvant chemotherapy followed by partial penectomy, right inguinal node dissection and bilateral pelvic node dissection with pathology revealing persistent metastatic disease. The patient had recurrent disease in his left groin and pelvis and was placed on cetuximab for 12 weekly doses. The patient experienced a near complete clinical and radiographical response after EGFR blockade. The patient had EGFR expression in his tissue at a low level and had absence of KRAS mutations. In the second patient who received EGFR blockade, there was progression while on therapy; this patient similarly had low levels of EGFR expression on immunohistochemistry. The third patient had treatment for refractory penile cancer with panitumumab and experienced partial response; however, the patient did develop recurrence after 2 months of treatment; this patient had moderate EGFR expression on tissue analysis. An interesting observation the authors of this study found was the difference in response to treatment between EGFR expression represented by immunohistochemistry and that by EGFR mRNA expression; however, given that this is a small case series, further larger studies will be needed to develop prediction tools to help select what patients would benefit most from therapy [29]. Another demonstration of the effect that EGFR targeted therapy has on penile cancer was made in a case series recently published by Carthon et al. In this group, 24 patients with advanced or metastatic penile cancer received EGFR-targeted therapy in the form of cetuximab, erlotinib or gefitinib (67% received cetuximab) following chemotherapy. Interestingly in this group, 3 out of 24 patients who received EGFR therapy after no response to conventional chemotherapy underwent consolidative surgery due to regression of their disease with combination of EGFR targeted therapy and chemotherapy. 962
Those three patients demonstrated improved overall survival compared to those who did not undergo consolidative surgery and two of the patients experienced long-term disease-free survival. In this retrospective cohort tissue, one limitation was that staining for EGFR was only performed in 13 of the 24 patients; although all 13 had EGFR positivity, no stratification based on degree of EGFR staining was described. Another observation from this study was the decrease in overall survival in patients with visceral or bone metastasis despite response to therapy [30]. A part of the EGFR signaling cascade, the KRAS gene has been studied with respect to sensitivity to anti-EGFR therapy [31]. Gou et al. took the tissue from 150 patients with penile SCC and identified overexpression of EGFR in 92% of those patients, while also finding only one patient with KRAS gene mutation [32]. This is important as it has been demonstrated in patients with colorectal cancer that KRAS gene mutation is associated with insensitivity to antiEGFR therapy [33]. The importance of developing biomarkers which will help stratify patients into groups that will benefit the most or least from therapy is essential and must be done in parallel to the discovery of novel targeted therapeutic agents [34]. The very low incidence of penile cancer results in the demonstrated paucity of literature and small number of patients described in case series and reviews to date. In order to better understand which patients may benefit from targeted therapies, larger multi-institutional and collaborative studies will need to be performed. COX-2 and prostaglandin E synthase 1 The anti-inflammatory group of medications, which includes aspirin, has been available for many years. Through the mass utilization of these medications by the general population, trends in the reduction of certain cancers have been observed, which have led efforts by scientists to understand the mechanism of action for this antineoplastic effect. The COX enzymes, also known as prostaglandin endoperoxide synthases, convert arachidonic acid into prostaglandins, which can be further converted, and produce the actions we are familiar with such as inflammation, platelet aggregation, bone resorption and maintenance of gastric and renal blood flow. There have been three isoforms of COX identified of which COX-1 and COX-2 are the best studied. COX-1 is expressed constitutively throughout the body, whereas COX-2 is an inducible enzyme mainly by hypoxia and tissue injury [35]. The pathway of COX inhibition occurs via two routes: the nonselective inhibition as seen with aspirin and ibuprofen which blocks both COX-1 and COX-2 and the selective inhibition through blockade of COX-2, utilizing drugs such as celecoxib. The analgesic effect of COX is mediated through COX-2, whereas the other vascular and gastrointestinal effects are mediated by COX-1. Thus, selective inhibition of COX-2 has been utilized in rheumatoid and osteoarthritis to allow for the beneficial effect of pain relief with a reduction in the side 2.3
Expert Opin. Drug Discov. (2014) 9(8)
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Novel targeted therapies for the treatment of penile cancer
effects such as gastroduodenal ulcers, impaired renal blood flow and increased risk of bleeding due to the reduction in platelet aggregation. In a meta-analysis of all of the clinical trials involving COX-2 inhibition, there was an increased risk of myocardial infarction seen with chronic use of COX-2 inhibitors. However, this risk is similar to that caused by other nonsteroidal anti-inflammatories such as ibuprofen when used long term [36]. The antineoplastic effect of COX inhibition has been found to be mediated primarily by blockade of COX-2. COX-2 is activated in response to tissue injury and results in a proinflammatory response. The cascade of events following activation of COX-2 causes recruitment of factors involved with angiogenesis such as VEGF. In addition to the resultant neovascularity, there is a decrease in apoptosis, an increase in cellular motility and decrease in the patients’ natural immune response to tumorigenesis [37]. There is an increased expression of COX-2 in a number of tumor types; however, it has been most studied in colorectal cancers. The activity of COX-2 inhibition has also been demonstrated in this tumor subtype. Recently, Shin et al. demonstrated the efficacy of combined EGFR and COX-2 inhibition in a head and neck SCC cell line. The combination therapy resulted in reduced progression compared to either agent alone. In a Phase I trial of chemoprevention with EGFR and COX-2 inhibition, Shin et al. showed a pathological response rate of 71% in patients with premalignant lesions that were treated with the dual therapy for chemoprevention [38]. Golijanin et al. determined tissue expression of COX-2 in penile carcinoma in situ, invasive SCC and metastatic SCC to the lymph nodes. They were able to confirm that there is an overexpression of COX-2 in all these penile carcinoma stages [39]. Utilizing this information and extrapolating from head and neck cancers as well as observations in gastrointestinal malignancies gives the basis for further studies of treating penile carcinoma with COX-2 inhibition. However, as is true for the other therapies mentioned, these will have to be validated prospectively and in randomized controlled trials to determine the true efficacy.
Tyrosine kinase inhibitors (sorafenib and sunitinib)
2.4
By utilizing combinations of targeted drug therapies, resistance mechanisms of tumors can be thwarted, resulting in improved survival for patients [40]. In this spirit, the application of wellstudied tyrosine kinase inhibitors, such as sorafenib and sunitinib as utilized in metastatic renal cell carcinoma, in patients with penile cancer is warranted [41]. To date, there is minimal prospective clinical trial evidence available; however, a small case series was published by Zhu et al. who described six patients with advanced penile cancer. In their series, all the patients had received two prior chemotherapy regimens and subsequently received either sunitinib or sorafenib. Of the six patients, one achieved a partial response and four had stable
disease. Serum SCC antigen as well as tissue microvessel density and Ki-67 levels were measured before and after therapy. In the patient who had a partial response, the serum SCC antigen level had a 95% reduction. In the other patients there was a reduction in microvessel density and Ki-67 levels [42]. This study by Zhu et al. combining treatment with diagnostics specific to penile cancer allows for direct observations of activity to be seen. This goes along with the concept of having molecular determinants of treatment efficacy aiding in selection of patients in the future who would benefit from therapy. Human papillomavirus There is an association between high risk HPV types and anogenital carcinomas. In penile cancer, the predominant HPV subtypes are 16 and 18 and these are found in 40% of patients [43]. These higher risk HPV types encode three oncogenic proteins, namely E5, E6, and E7. The E5 protein has been associated with activation of EGFR in addition to other receptor tyrosine kinases. The E7 proteins degrade the retinoblastoma tumor suppressor. This along with the E6 proteins targeting of the p53 tumor suppressor results in cell proliferation. In addition, these oncoproteins result in increased angiogenesis and other processes involved with the EMT that is associated with invasive and metastatic carcinoma [44]. Based on the findings that HPV infection is associated with both premalignant and malignant cervical cancer, a vaccine against HPV has been developed and thus far has been shown to be effective in up to 99% of patients [45]. These positive results in randomized trials have led to the FDA approval of the vaccine which is indicated for females aged 9 -- 26 for the prevention of cervical, vulvar and vaginal cancers, and for males and females aged 9 -- 26 for the prevention of anal cancer, precancerous or dysplastic lesions and genital warts caused by HPV types 6,11, 16 and 18 [46,47]. In addition to the vaccination, there have been efforts to target the specific actions of the HPV oncoproteins (E6 and E7) and their pathways. Thus far there have been few promising studies that have shown efficacy with this type of approach; however, ongoing research projects investigating the different pathways to alter this mechanism of oncogenesis are in progress [44]. The role of HPV as a determinant of prognosis in penile cancer patients is unclear [48]. In patients with head and neck carcinoma, survival rates were improved in those who were found to have tissue with the presence of HPV [49]. In a case series of 82 patients with penile cancer, men with HPVpositive tumors had a non-statistically significant decreased rate of metastasis compared to those without HPV [50]. A study by Lont et al. looked at 171 patients with penile cancer and tested their tissue for high-risk HPV. They found that 29% of the tumors were positive for high-risk HPV, and there was a significant difference in 5-year disease-specific survival with a reduction in risk of dying from disease (HR = 0.14, p=0.01) in those patients who were positive for high-risk HPV [51]. The findings in these small retrospective studies 2.5
Expert Opin. Drug Discov. (2014) 9(8)
963
G. Agarwal et al.
EGF
PGE2
Arachidonic COX-2 Acid
EGFR
PI3K
HIF1 alpha
MMP
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Cell migration and invasion
Survivin
VEGF Degradation
Decreased apoptosis angiogenesis
E-cadherin
Figure 1. Schematic representation of the signaling pathway for EGF and prostaglandins responsible for neoplasia. HIF1-a: Hypoxia-inducible factor 1-a; PGE2: Prostaglandin E2; PI3K: Phosphoinositide 3-kinase.
warrant further prospective multi-institutional collaborations in order to better understand not only the association between high-risk HPV infection and improved survival but also the mechanistic process causing this [52]. An understanding of the pathway of events involved allows for the development of targeted therapies [53].
Lymphangiogenesis and the mammalian target of rapamycin
2.6
The lymph node status of patients with invasive penile SCC is crucial in determining a patient’s treatment plan and plays a major role in the clinician’s assessment of a patient’s prognosis. Understanding the molecular mechanisms responsible for lymph node metastasis would possibly allow for a better assessment of which patients may display more aggressive disease than others. Understanding lymphangiogenesis would also leave this as another avenue for targeted therapy [54]. This will also aid in selection of which patients would benefit from an upfront lymph node dissection versus a delayed approach. Some investigators believe that existing peritumoral lymph vessels do not play a major role in the development of metastasis [55], whereas others believe intratumoral lymphangiogenesis has a significant association with nodal metastasis [56], Naumann et al. did not find an association between lymph vessel density at peritumoral or intratumoral sites and the presence of lymph node metastasis in patients with penile SCC [55]. However, what they found as the major driver of lymph node metastasis was the presence of lymphovascular invasion. This is contrary to findings in the head and neck carcinoma literature where the development of intratumoral lymphatics was found to be highly associated with both metastasis and prognosis in those patients [56]. Investigation of other targets for therapy to prevent or treat lymph node metastasis in penile cancer led to the evaluation of mammalian target of rapamycin (mTOR) expression in the 964
tissue of these patients. Ferrandiz-Pulido et al. performed immunohistochemical staining on the tissue of 67 patients with invasive penile cancer. They found an overexpression of phosphorylated mTOR in those patients with lymph node disease [57]. Chaux et al. similarly looked at 112 cases of patients with penile carcinoma evaluating the expression of markers along the mTOR pathway (phosphatase and tension homolog, phosphorylated AKT and phosphorylated mTOR) [58]. They found aberrant expression of these markers, indicating a role for further study of the mTOR pathway in penile cancer. Although mTOR inhibition has not been studied for the treatment of penile SCC, corollaries from the head and neck literature make this targeted treatment a worthwhile agent to study further. Ekshyyan et al. used a mouse model of SCC of the head and neck to study the anti-lymphangiogenesis effects of mTOR inhibition in vivo. They found that rapamycin (an mTOR inhibitor) significantly decreased lymphatic vessel density and decreased lymph node metastasis [59]. Patel et al. used a mouse model for head and neck SCC to further characterize the association between mTOR pathways and metastatic disease as well as the role of mTOR inhibition for treatment of the disease. They found that mice that had tumor spread to their lymph nodes had elevated mTOR activity and that inhibition with rapamycin decreased lymphangiogenesis in the primary tumors and prevented metastatic spread of disease, thus improving survival [60]. Future studies should incorporate the study of lymphangiogenesis in penile cancer and the expression of mTOR in tissue of these patients to further characterize the role of such markers in the prognosis and response to treatment. 3.
Expert opinion
Penile cancer, although rare in the USA, is a uniformly lethal disease when it presents in the advanced stages. With a greater
Expert Opin. Drug Discov. (2014) 9(8)
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Novel targeted therapies for the treatment of penile cancer
understanding of tumor biology and the human body’s innate defense mechanisms to prevent neoplasia, the advent of targeted therapy has entered a rapidly evolving era of study (Figure 1). The balance between toxicity of treatment and efficacy will also continue to improve as the agents become more specific. Of paramount importance is the discovery of biomarkers alongside the targeted therapies so that when performing clinical trials these markers can be correlated with efficacy and response to therapy. This will allow future patients to be selected for treatment with specific agents based on their tumor histology and molecular signature. An understanding of the process by which a normal cell undergoes malignant transformation in patients who develop penile cancer can be gained when studying the interactions between high-risk HPV and tissue from the patients afflicted with the disease. In fact, the research involved with HPV and its association with premalignant and malignant lesions led to the introduction of an HPV vaccine which, by 2040, will result in the virtual elimination of cervical cancer in the USA [44]. Targeted therapies should be developed at every stage where intervention is possible in a patient’s life. This includes behavior and lifestyle modifications, an understanding of risk factors and development of vaccines for prevention of disease. The next stage would be to develop biomarkers for improved detection and stratification of patients who harbor aggressive disease. After patients are stratified, an improvement and more specific targeted treatment of disease in a neoadjuvant and adjuvant settings should be sought after. Currently, the magnitude of advancement is at a staggering pace and with continued efforts our patients will see an improvement in their survival. Some of the most promising therapies are those that target the EGFR. These agents have been utilized in a small series of patients; however, extrapolating from randomized clinical trial evidence in the head and neck SCC literature as well as small case series demonstrating partial and some complete responses, this therapy warrants multi-institutional validation studies. In addition, the role of
COX-2 inhibition in the chemoprevention and treatment of penile carcinoma deserves continued attention. Moreover, targeting the mTOR pathway in patients with invasive penile cancer may have not only a primary role but also an additive effect with other therapies. Ultimately, a combination of chemotherapy and targeted agents will be adopted, starting with those with advanced tumors, and ultimately it would be utilized in the neoadjuvant setting. A better understanding of the molecular pathways involved with tumorigenesis in penile cancer as well as an understanding of metastatic spread of disease concurrent with immunohistochemical analysis to identify markers of disease alongside clinical trials that treat patients with targeted agents needs to occur before widespread adoption of these novel therapies. For instance, EGFR expression is present in almost all patients with penile cancer; thus, further analysis of the degree of expression as a marker of treatment efficacy needs to occur as in its current state; this may not be a good marker for selecting patients or even evaluating response to therapy. Within the next decade, a personalized approach to treat patients with invasive penile carcinoma will occur. Determining which patients should be observed after primary treatment of a penile tumor and who should go on to lymphadenectomy can be aided by developing reliable markers of disease aggressiveness. The patient-tailored approach using molecular markers will allow for not only decreased morbidity by avoiding overtreatment but also improved survival by selecting patients who are most likely to benefit from additional therapy.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
Expert Opin. Drug Discov. (2014) 9(8)
965
G. Agarwal et al.
Bibliography
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29
2.
Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol 2010;57(6):1002-12
3.
Kacker S, Frick KD, Gaydos CA, et al. Costs and effectiveness of neonatal male circumcision. Arch Pediatr Adolesc Med 2012;166(10):910-18
4.
Burt LM, Shrieve DC, Tward JD. Stage presentation, care patterns, and treatment outcomes for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 2014;88(1):94-100
5.
Moses KA, Winer A, Sfakianos JP, et al. Contemporary management of penile cancer: greater than 15 year MSKCC experience. Can J Urol 2014;21(2):7201-6
6.
Spiess PE; National Comprehensive Cancer Network. New treatment guidelines for penile cancer. J Natl Compr Canc Netw 2013;11(Suppl 5):659-62
7.
Protzel C, Seitz AK, Hakenberg OW, et al. [Neoadjuvant, adjuvant and palliative chemotherapy of penile cancer]. Urologe A 2013;52(11):1556-60.62-3
8.
Zanetta G, Lissoni A, Pellegrino A, et al. Neoadjuvant chemotherapy with cisplatin, ifosfamide and paclitaxel for locally advanced squamous-cell cervical cancer. Ann Oncol 1998;9(9):977-80
9.
..
10.
11.
966
Sonpavde G, Pagliaro LC, Buonerba C, et al. Penile cancer: current therapy and future directions. Ann Oncol 2013;24(5):1179-89 This article provides a nice summary of recent literature regarding the treatment of advanced penile cancer. Nicholson S, Hall E, Harland SJ, et al. Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/ 001). Br J Cancer 2013;109(10):2554-9 Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic
..
penile cancer: a phase II study. J Clin Oncol 2010;28(24):3851-7 This is a landmark article detailing a very important clinical trial utilizing neoadjuvant chemotherapy for penile cancer.
12.
Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Cancer Netw 2013;11(5):617-24
13.
Pietrantonio F, Biondani P, Verzoni E, et al. Management of advanced genitourinary tumors. Tumori 2012;98(2):264-6
14.
Gunia S, Erbersdobler A, Hakenberg OW, et al. C-MET is expressed in the majority of penile squamous cell carcinomas and correlates with polysomy-7 but is not associated with MET oncogene amplification, pertinent histopathologic parameters, or with cancer-specific survival. Pathol Res Pract 2013;209(4):215-20
15.
.
16.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74 This article is an essential read for any reader interested in having a better understanding of carcinogenesis. Umbas R, Schalken JA, Aalders TW, et al. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 1992;52(18):5104-9
17.
Campos RS, Lopes A, Guimaraes GC, et al. E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology 2006;67(4):797-802
18.
Nelson R. Potential prognostic markers in penile cancer. Lancet Oncol 2006;7(5):369
19.
20.
Pedersen MW, Meltorn M, Damstrup L, et al. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol 2001;12(6):745-60 Chaux A, Cohen JS, Schultz L, et al. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded
Expert Opin. Drug Discov. (2014) 9(8)
archival tissues. Hum Pathol 2012;43(10):1590-5 21.
Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366(1):2-16
22.
Haley JD, Gullick WJ. EGFR signaling networks in cancer therapy. Humana Press, New York, NY; 2008. p. 221-35 This is a detailed book that goes through EGFR from start to finish regarding discovery of current ways to target it in multiple solid organ malignancies.
.
23.
Wang D, Su L, Huang D, et al. Downregulation of E-Cadherin enhances proliferation of head and neck cancer through transcriptional regulation of EGFR. Mol Cancer 2011;10:116
24.
Zuo JH, Zhu W, Li MY, et al. Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin. J Cell Biochem 2011;112(9):2508-17
25.
Baker CH, Kedar D, McCarty MF, et al. Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J pathol 2002;161(3):929-38
26.
Burtness B, Goldwasser MA, Flood W, et al. Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/ recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23(34):8646-54
27.
Necchi A, Nicolai N, Colecchia M, et al. Proof of activity of anti-epidermal growth factor receptor-targeted therapy for relapsed squamous cell carcinoma of the penis. J Clin Oncol 2011;29(22):e650-2 This is one of the first descriptions of efficacy of anti-EGFR therapy in penile cancer.
.
28.
Giannatempo P. Early results of the pilot study with the anti-epidermal growthfactor receptor (EGFR) monoclonal antibody panitumumab in patients (PTS) with multi-relapsed or refractory
Novel targeted therapies for the treatment of penile cancer
29.
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
30.
Brown A, Ma Y, Danenberg K, et al. Epidermal growth factor receptortargeted therapy in squamous cell carcinoma of the penis: a report of 3 cases. Urology 2014;83(1):159-65 Carthon BC, Ng CS, Pettaway CA, et al. Epidermal growth factor receptortargeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int 2013
31.
Plesec TP, Hunt JL. KRAS mutation testing in colorectal cancer. Adv Anat Pathol 2009;16(4):196-203
32.
Gou HF, Li X, Qiu M, et al. Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma. PLoS One 2013;8(4):e62175 This is a nice article highlighting the EGFR pathway.
.
33.
34.
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360(14):1408-17 Carlson BC, Hofer MD, Ballek N, et al. Protein markers of malignant potential in penile and vulvar lichen sclerosus. J Urol 2013;190(2):399-406
35.
Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004;56(3):387-437
36.
Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086
37.
..
38.
39.
Pruthi RS, Derksen E, Gaston K. Cyclooxygenase-2 as a potential target in the prevention and treatment of genitourinary tumors: a review. J Urol 2003;169(6):2352-9 This is a very nice review of COX-2 and its role in multiple urologic cancers. Shin DM, Zhang H, Saba NF, et al. Chemoprevention of head and neck cancer by simultaneous blocking of epidermal growth factor receptor and cyclooxygenase-2 signaling pathways: preclinical and clinical studies. Clin Cancer Res 2013;19(5):1244-56 Golijanin D, Tan JY, Kazior A, et al. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are
of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 2001;91(12):2315-21
overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res 2004;10(3):1024-31
squamous cell Carcinoma (SCC) of the Penis. J Urol 2013;189(No. 4S):e309 40.
Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology 2009;76(5):350-4
51.
Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006;119(5):1078-81
41.
Mooney D, Paluri R, Mehta A, et al. Update in systemic therapy of urologic malignancies. Postgrad Med 2014;126(1):44-54
52.
42.
Zhu Y, Li H, Yao XD, et al. Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: a preliminary report. Urol Int 2010;85(3):334-40
Fonseca AG, Soares FA, Burbano RR, et al. Human papilloma Virus: prevalence, distribution and predictive value to lymphatic metastasis in penile carcinoma. Int Braz J Urol 2013;39(4):542-50
53.
Connolly K, Manders P, Earls P, et al. Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control. Cancer Treat Rev 2014;40(2):205-14
54.
Karpanen T, Alitalo K. Lymphatic vessels as targets of tumor therapy? J Exp Med 2001;194(6):F37-42
55.
Naumann CM, Al-Najar A, Alkatout I, et al. Lymphatic spread in squamous cell carcinoma of the penis is independent of elevated lymph vessel density. BJU Int 2009;103(12):1655-9.discussion 59
56.
Maula SM, Luukkaa M, Grenman R, et al. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 2003;63(8):1920-6
57.
Ferrandiz-Pulido C, Masferrer E, Toll A, et al. mTOR signaling pathway in penile squamous cell carcinoma: pmTOR and peIF4E over expression correlate with aggressive tumor behavior. J Urol 2013;190(6):2288-95
58.
Chaux A, Munari E, Cubilla AL, et al. Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases. Histopathology 2014;64(6):863-71
59.
Ekshyyan O, Moore-Medlin TN, Raley MC, et al. Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models. BMC Cancer 2013;13:320
60.
Patel V, Marsh CA, Dorsam RT, et al. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Res 2011;71(22):7103-12
43.
.
Flaherty A, Kim T, Giuliano A, et al. Implications for human papilloma virus in penile cancer. Urol Oncol 2014;32(1):53 e1-8 This is a nice review of the role that human papillomavirus has in penile cancer.
44.
Hellner K, Munger K. Human papillomaviruses as therapeutic targets in human cancer. J Clin Oncol 2011;29(13):1785-94
45.
Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a doubleblind, randomised study in young women. Lancet 2009;374(9686):301-14
46.
Merck & Co. I. Highlights of prescribing information for gardisil. product information packet 2011
47.
de Bruijn RE, Heideman DA, Kenter GG, et al. Patients with penile cancer and the risk of (pre)malignant cervical lesions in female partners: a retrospective cohort analysis. BJU int 2013;112(7):905-8
48.
49.
50.
Zhai JP, Wang QY, Wei D, et al. [Association between HPV DNA and disease specific survival in patients with penile cancer]. Zhonghua Yi Xue Za Zhi 2013;93(34):2719-22 O’Rorke MA, Ellison MV, Murray LJ, et al. Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 2012;48(12):1191-201 Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis
Expert Opin. Drug Discov. (2014) 9(8)
967
G. Agarwal et al.
Affiliation
Downloaded by [University of California, San Diego] at 08:08 05 September 2015
Gautum Agarwal1 MD, Shilpa Gupta1 MD & Philippe E Spiess†2 MD MS FACS † Author for correspondence 1 Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, FL, USA 2 Associate member, Moffitt Cancer Center, Department of Genitourinary Oncology, 12902 Magnolia Drive office 12538, Tampa, FL 33612, USA Tel: +1 813 745 8343; Fax: +1 813 745 8494; E-mail: [email protected]
968
Expert Opin. Drug Discov. (2014) 9(8)
