Management of Urologic Cancer

Focal Therapy and Tissue Preservation

Mark P. Schoenberg, Kara L. Watts, Mark P. Schoenberg, Kara L. Watts

• Publisher: Wiley-Blackwell
• Year: 2017
• ISBN:
  9781118868089
• Edition: 1
• Topic: Médecine
• Subtopic: Urologie

Managing urologic cancer by preserving, as opposed to removing, affected tissue, is rapidly becoming the favoured choice for urologists and oncologists. Discover all available options and how to achieve the best possible patient management with this expert guide to the area. The editor, Mark Schoenberg, is an internationally-renown expert in this exciting new area and has recruited an outstanding team featuring some of the leading urologists/oncologists in North America and Europe to assist him.

1
Cancer Genetics, Cancer Biology, and Tumor Growth and Metastasis: The Interaction of Cancer and Its Host Environment

Mark C. Markowski, MD, PhD, and Kenneth J. Pienta, MD

Department of Medical Oncology, John Hopkins University, Baltimore, MD, USA

Renal Cell Carcinoma

Premalignant Lesions

Unlike prostate cancer, precursor lesions for renal cell carcinoma (RCC) are not well understood. Renal intraepithelial neoplasia (RIN) and dysplastic changes have been described in the literature [1]. Some of these lesions have common genetic alterations with RCC, share spatial orientation, and have a premalignant appearance, which suggests an evolutionary relationship to carcinoma [2]. Given the sparse data and limited characterization, it is likely that this premalignant state is short lived or that the majority of RCCs occurs de novo. This further suggests that the time from genetic insult to overt carcinoma is rapid, emphasizing the need for early surgical intervention for curative intent.

Molecular Pathogenesis

Almost 100 years ago, Von Hippel and Lindau described a familial pattern of vascularized retinal growths, which was later recognized to be part of an autosomal dominant disorder. These patients were predisposed to develop hemangioblastomas, pheochromocytomas, and clear‐cell RCC. In 1993, the VHL gene was discovered at 3p25.3, a region that is frequently deleted in RCC. Somatic mutations, promoter methylation, or loss of heterozygosity of VHL is found in up to 90% of sporadic RCCs [3,4]. The VHL protein is best known for its role as the substrate recognition component of an E3 ligase and targeting of hypoxia inducible factors (HIF) for ubiquitination and degradation [5]. In hypoxic environments or in the absence/inactivation of VHL protein, the alpha subunit of HIF heterodimerizes with HIFβ and translocates to the nucleus, and transcribes a number of genes including VEGF, PDGF‐β, and TGF‐α (Figure 1.1) [6]. The unregulated activation of this pathway is a main driver of angiogenesis, invasion, and metastasis in the majority of sporadic RCCs.

Figure 1.1 Molecular dysregulation of renal cell carcinoma. Under normal hypoxic conditions or in the presence of VHL mutations, HIFα and HIFβ form a heterodimer, translocate to the nucleus and function as a transcription factor. Small molecule tyrosine kinase inhibitors (TKIs), Sunitinib and Pazopanib, or monoclonal antibodies (Bevacizumab) can abrogate VEGF signaling in RCC. TKIs can also attenuate the PI3K/mTOR and MAPK pathways shown. Temsirolimus and everolimus can directly antagonize mTOR signaling, inhibiting growth in certain RCCs.

Adapted from Clin Cancer Res. December 15, 2006; 12(24):7215–7220.

Targeting of the VEGF pathway has been mainstay of treatment for metastatic or unresectable RCC. Small molecule tyrosine kinase inhibitors (TKI) have been successful at disrupting VEGF signaling, resulting in improved patient survival in the metastatic setting. VEGF and PDGFβ can stimulate the proliferation and migration of endothelial cells. The establishment of an enriched blood supply can facilitate the establishment of metastatic niches and lead to disseminated disease. As a result of this high metastatic potential, there is no currently approved neoadjuvant systemic approach for RCC using targeted therapies such as sunitinib or pazopanib. The use of these agents is also not approved in the adjuvant setting after nephrectomy. Multiple studies have failed to show a survival benefit of adjuvant TKI use or immunotherapy after definitive surgery underscoring the importance of early intervention with upfront surgery [7].

Loss of chromosome 3p is the most frequent genetic mutation in RCC. In addition to VHL, this region also contains the gene, PBRM1 (3p21). PBRM1 is a purported “gatekeeper” gene and plays a significant role in DNA repair, replication, and transcription. Somatic mutations have been found in 41% of clear‐cell renal carcinomas but may be has high as 50% [8,9]. Loss of the PBRM1 has been correlated with advanced stage, higher‐grade disease, and worse patient outcomes [10]. Alterations of chromosome 3p may mark a key genetic event, either inherited or acquired, that drives early tumorigenesis. Multiple genetic changes have been observed in RCC, including gain of 5q containing TGFB1 and CSF1R and deletion of 14q harboring the tumor suppressor candidate, NRXN3.(11) Loss of 14q was associated with higher‐grade disease and worse survival [11,12].

mTOR is a serine/threonine kinase that couples with adapter proteins forming two distinct complexes, mTORC1 and mTORC2. mTORC1 activation has been implicated in >50% of RCCs [13]. Interestingly, HIF‐1α has been shown to increase the expression of REDD1, a known inhibitor of mTORC1 [14]. Under hypoxic conditions, the stabilization of HIF‐1 levels lead to the inhibition of mTOR signaling. This inhibition is dependent on the gene products of TSC1 (tuberous sclerosis complex 1) and TSC2 [14]. Mutations in TSC1 and PTEN may abrogate the effect of the HIF‐1 signaling axis on mTOR inhibition, resulting in a second and distinct mechanism of carcinogenesis [15].

Everolimus binds to FKBP‐12 and inhibits the activity of mTORC1. A Phase III trial that examined the effect of everolimus in patients with metastatic RCC who had progressed on TKI therapy was stopped early when 37% of the total progression events were shown in the everolimus group compared to 65% in the placebo arm [16]. In 2010, the final results of the trial showed a 3‐month progression‐free survival advantage following treatment with everolimus [17]. Temsirolimus, an intravenous inhibitor of mTORC1, increased overall survival in untreated patients with metastatic RCC and poor prognostic features [18]. Similar to TKI therapy, there is no role for mTOR inhibitors in the treatment of localized RCC.

The discovery of TKIs has revolutionized the treatment of metastatic disease and improved overall survival. Surgery remains the main treatment for localized disease. With the development of next‐generation TKIs, targeted therapy may complement a surgical approach for early‐stage disease.

Bladder Cancer

Bladder cancer is the fourth‐most common neoplasm in males, consisting predominantly of urothelial carcinoma. The pathological stage of the tumor distinguishes between nonmuscle‐invasive disease and muscle‐invasive disease. Use of “molecular grading” may also aid conventional staging parameters and further define muscle‐ versus nonmuscle‐invasive disease. Common alterations in cell‐cycle regulation and growth pathways of bladder cancers are described next.

Cell‐Cycle Regulation

Alterations in cell‐cycle regulation pathways were found in approximately 90% of all muscle‐invasive bladder cancers [19]. In this study, the Cancer Genome Atlas Research Network (CGARN) found that TP53 mutations were found in 49% of cancers. Other studies have found that mutations in TP53 were associated with recurrence of nonmuscle‐invasive bladder cancer as well as disease progression and poor prognosis [20,21]. There are conflicting data regarding the utility of p53 alteration when used to direct the administration of neoadjuvant therapy [22–24]. Although a common event in carcinogenesis, using p53 alterations as a sole biomarker to dictate treatment is of unclear clinical significance.

Studies have also incorporated other cell‐cycle regulators in conjunction with p53 to better risk stratify patients. Garcia del Muro et al. examined the relationship of p53 and p21 overexpression to survival [25]. P53 regulates p21 expression, a cyclin‐dependent kinase inhibitor, which can arrest cell growth by inhibiting Rb phosphorylation. Patients with T2‐T4a, N0 disease received neoadjuvant chemotherapy followed by either radiation or surgery, depending on residual disease status. Patients harboring tumors that overexpressed p53 and p21 had a worse overall survival compared to patients with normal expression levels. A retrospective study showed that patients with pT1 disease treated with radical cystectomy were 24 and 27 times more likely to have disease relapse and cancer‐specific death if alterations were found in p53, p27, and Ki‐67 expression [26]. The combination of increased p53 and pRB expression with alter...