Advanced Basal Cell Cancer: Concise Review of Molecular Characteristics and Novel Targeted and Immune Therapeutics

M. Nikanjam; P. R. Cohen; S. Kato; J. K. Sicklick; R. Kurzrock


Ann Oncol. 2018;29(11):2192-2199. 

In This Article

Genomic Landscape/Alterations and Development of Rational Therapeutics

Hedgehog Pathway Rationale, Targeted Therapeutics, and Resistance

The Hedgehog signaling pathway is important for basal cell proliferation and tumor growth. Normal signaling is initiated by the binding of Hedgehog ligands (Sonic, Desert, or Indian Hedgehog) to their receptor, patched 1 (PTCH1). In turn, the PTCH1 tumor suppressor protein releases its inhibition of the smoothened (SMO) proto-oncoprotein. Once SMO inhibition is removed, downstream signaling occurs through a series of interacting proteins, including suppressor of fused homolog (SUFU), which ultimately leads to activation of the GLI family of transcription factors (Figure 1).[22] TP53, while not part of the Hedgehog pathway, can interact with and inhibit GLI transcription factors[23] and Hedgehog signaling can also inhibit TP53 tumor suppression.[24] Thus mutations in TP53 can further potentiate Hedgehog signaling in BCC.

Figure 1.

Hedgehog signaling pathway. (A) In the absence of hedgehog protein (Hh), patched 1 (PTCH1) inhibits smoothened (SMO) and suppressor of fused homolog (SUFU) inhibits the GLI transcription factors (GLI) leading to degradation of GLI and blockage of target gene transcription. (B) In the presence Hh, the inhibition of PTCH1 on SMO is released. SMO inhibits SUFU which releases GLI to move to the nucleus and initiates transcription. (C) Advanced basal cell cancers have PTCH1 mutations in approximately 70% of tumors as compared with 30% in metastatic basal cell cancer while SMOmutations are present in 10%–20% of tumors [28, 30, 31] (Table 1). PTCH1 and SMO mutations activate the Hedgehog pathway. PTCH1 mutations inactivate PTCH1 hence abrogating its inhibitory effect on SMO. SMO mutations directly activate SMO. Both PTCH1 and SMO mutations result in inhibition of SUFU which then allows GLI-mediated transcription of target genes. In the presence of SMO inhibitors (vismodegib, sonidegib, saridegib), SUFU remains active and inhibits the GLI transcription factors, leading to degradation of GLI and blockage of target gene transcription. Itraconazole and arsenic trioxide inhibit the downstream effector GLI.

Mutations in PTCH1 or much less commonly SMO can result in constitutive activation of the pathway. Mutations leading to loss of heterozygosity on chromosome 9q22.3 and UV-signature C->T substitutions in the PTCH1 gene have been associated with constitutive activation of the pathway.[25] Loss of the PTCH1 gene can induce tumor formation and SMO overexpression can create skin tumors in mice[26,27] with the first report linking SMO activating mutations in the Hedgehog signaling pathway to BCC formation presented by Xie et al..[27] A study of 42 BCCs showed PTCH1mutations in 67% and TP53 alterations in 40% of patients, with only 10% having mutations in SMO.[28] A whole-genome microarray analysis of 20 BCCs found increased expression of PTCH1 and GLI2.[29] Genomic profiling with whole exome sequencing of 293 BCCs showed a high mutation rate with 85% of tumors harboring mutations in the Hedgehog pathway. Overall, 73% of mutations were in PTCH1; 20%, SMO; 8%, SUFU; and 61%, TP53.[30] In addition, comprehensive genomic profiling of 60 metastatic BCCs [315 gene next-generation sequencing (NGS) panel] demonstrated a high tumor mutational burden (TMB), with 79% harboring TP53mutations; 32%, PTCH1; and 17%, SMO[31] (Table 1). Thus, metastatic BCC appears to have lower rate of PTCH1 mutations as compared with advanced BCC. Phosphoinositide 3-kinase (PI3K) and AKT signaling are also essential for GLI-dependent Hedgehog signaling, and stimulation of PI3-kinase by insulin-like growth factor-1 can potentiate GLI transcription.[32]

Resistance can develop to SMO inhibitors through secondary mutations in SMO that directly impair drug binding or otherwise activate SMO.[33] Resistance occurs to a lesser extent through alterations in downstream effectors SUFU and GLI.[34] Specific secondary mutations in SMO that result in acquired resistance to SMO inhibitors include A459V, C469Y, D473G, F460L, H231R, I408V, L412F, Q477G, S533N, T241M, V321M, W281C, W535L.[33,34] A patient with multiple genomic alterations as can occur with a high tumor mutation burden may also theoretically be resistant to a single targeted agent such as a SMO inhibitor, presumably due to the presence of additional genomic abnormalities that supplant the role of the Hedgehog pathway. Taken together, BCCs appear to be addicted to Hedgehog signaling, but if resistance alterations occur, combination therapy may be needed to avert progression.

Current efforts and clinical trials are focused on targeting the Hedgehog signaling pathway. Table 1 summarizes clinical trials for metastatic BCC from[35–40]

Vismodegib and Sonidegib (EMA- and FDA-approved Hedgehog Inhibitors)

Vismodegib (Genentech-Roche) is an oral small-molecule inhibitor of SMO. It is EMA- and FDA-approved for adults with metastatic BCC in addition to those with locally advanced disease that has recurred after surgery, non-surgical candidates, or non-radiation candidates. It is given as a single dose at 150 mg daily. A phase I study in solid tumors found a 58% response rate for advanced BCC; median duration of response was 12.8 months.[38] The expansion cohort of the phase I study had 18 patients with metastatic BCC who had a 50% overall response rate to therapy.[41] Phase II data from the STEVIE study of vismodegib in patients with advanced BCC demonstrated that the objective response rate in metastatic disease was 38% (7%, CR) and median progression-free survival was 13.1 months.[36] A separate phase II study of 33 patients with metastatic BCC carcinoma found a response rate of 30% with a median progression-free survival of 9.5 months.[37] Thus response rates may be slightly lower in metastatic BCC as compared with advanced BCC. The most common adverse effects experienced by patients taking vismodegib in the phase 1 trial were muscle spasms, fatigue, alopecia, dysgeusia, and nausea.[38] All patients experienced treatment related adverse events in the phase II study; however, these were grade 2[42] or lower in almost half of the patients.[37]

Sonidegib (LDE225, Novartis, Basel, Switzerland) is a distinct small-molecule inhibitor of SMO and is approved by the EMA and the FDA as a single daily oral dose of 200 mg for patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. In the phase II trial for advanced BCC, doses of 200 and 800 mg were tested. Although the overall response rate for locally advanced disease was 57.5% in the 200-mg arm as compared with the 43.8% seen in the 800-mg arm, this did not hold for metastatic BCC where responses of 17% were seen in the 800-mg group versus 7.7% in the 200-mg group.[35] Thus higher doses may be indicated for metastatic disease. The lower responses rate in metastatic BCC may be due to the lower PTCH1mutation rate compared with that in locally advanced disease. Nearly all patients on the phase II trial of sonidegib experienced an adverse event. The most common events were muscle spasms, alopecia, dysgeusia, nausea, increased creatine kinase, fatigue, weight loss, decreased appetite, myalgia, and vomiting. Discontinuation due to adverse events occurred in 27.8% (200 mg) and 37.3% (800 mg) of patients.[35]

Other Hedgehog inhibitors

Saridegib (IPI-926, Infinity Pharmaceuticals Inc., Cambridge, MA, USA) is a small molecular inhibitor of SMO that is in clinical trials. A phase 1 included 39 patients with BCC, 19 of whom had metastatic BCC. While eight of the patients with advanced BCC had a response, there were no responses in the group with metastatic disease[39] consistent with the lower responses for metastatic disease observed for sonidegib and vismodegib. Overall treatment was generally well tolerated and the most common clinical adverse events were fatigue, nausea, and alopecia, with the vast majority of these less than grade 2.

Itraconazole is an azole antifungal but has also been found to be an inhibitor of GLI.[43] In a phase II study of non-metastatic BCC, 21% of patients treated with itraconazole had a response.[44] Arsenic trioxide can also antagonize the activating GLI transcription factors (GLI1 and GLI2), as well as reduce steady state levels of GLI2, a primary downstream effector of Hedgehog-mediated transcription.[45] A pilot study of arsenic trioxide in BCC is ongoing (NCT01791894). A clinical trial of itraconazole and arsenic trioxide in patients with advanced BCC is also ongoing (NCT02699723). However, a pilot study of five patients with metastatic BCC treated with arsenic trioxide and itraconazole showed no objective responses.[46]

Immune Modulators (Checkpoint Inhibitors) Rationale and Therapeutics

Biomarkers for response to checkpoint inhibitors may include programmed death ligand 1 (PD-L1) amplification, PD-L1 expression by immunohistochemistry, and high TMB.[47–53] All of these have been described in some metastatic BCCs.[6,54,55]

Tumor Mutational Burden (TMB)

Many non-small-cell lung cancers[47] and melanomas[49] have been reported to have high TMB (≥20 Mut/Mb) which has been linked to better responses to immunotherapies.[56] BCC has been reported to have a median 47.3 Mut/Mb as compared with 13.5 for melanoma and 7.2 Mut/Mb for lung cancer.[55,57] Genomic profiling with whole exome sequencing of BCCs[30] and more targeted genomic profiling of metastatic BCC showed high TMBs as compared with other cancers.[58] These mutations were described as consistent with an UV light pattern of damage and result in the higher TMBs seen in mBCC. The high TMB in BCCs might be expected to give superior responses to immunotherapy and is consistent with recent reports of high response rates in advanced BCC, albeit in small numbers of patients.[54,56,59]

PD-L1 Expression

PD-L1 is expressed on the surface of immune cells and binds to the receptor PD-1 to attenuate immune responses and promote peripheral tolerance. Cancer cells can up-regulate PD-L1 on tumor cells and tumor infiltrating lymphocytes (TILs) in order to escape the immune system. A study of PD-L1 expression on tumor cells and TILs demonstrated that treated BCCs express greater PD-L1 positivity (>5% by IHC) compared with untreated BCCs. Overall, when comparing treated versus untreated BCCs, 32% versus 4% expressed PD-L1 in tumor cells; 37% versus 11%, for PD-L1 expression on TILs.[54] In a study of 40 aggressive or recurrent BCCs, 22% demonstrated PD-L1 expression on tumor cells and 82% demonstrated PD-L1 expression on TILs and associated macrophages.[60]

Case reports have shown responses to PD-1 blockade for metastatic BCC treated with the anti-PD1 pembrolizumab or nivolumab.[6,60,61] The patient successfully treated with nivolumab following vismodegib, sonidegib, cytotoxic chemotherapy, and a PI3K inhibitor, had both a high TMB and PD-L1 amplification in their tumor;[6] interestingly, in this patient, while his metastatic disease, which harbored very high TMB (103 Mut/Mb) and had PD-L1 amplification by NGS, showed an excellent ongoing response to nivolumab, new superficial BCC appeared in sun-exposed skin areas.[62] For four patients treated with anti-PD-1 therapy at UC San Diego, median progression-free survival was 10.7 months and 75% had an objective response[56].A phase II clinical trial is currently underway investigating the role for pembrolizumab with or without vismodegib in metastatic or unresectable basal cell carcinoma (NCT02690948). A phase II trial of the novel PD-1 inhibitor REGN2810 in locally advanced or metastatic BCC is also underway (NCT03132636) with an ongoing partial response of more than 12 months reported in one patient in the phase 1 trial (NCT0238212).[40]

Other Targets

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that is important for progression of the cell cycle, angiogenesis, metastasis, angiogenesis, and apoptosis reduction. Strong expression is seen on 38% of basal cell carcinomas with weak expression in an additional 19%.[63] A case report demonstrated stabilization of disease in two patients with metastatic BCC given the EGFR inhibitor cetuximab.[64]

Genomic profiling with whole-exome sequencing of 293 basal cell carcinomas also identified additional driver mutations in 85% of BCCs including: MYCN (30%), PPP6C(15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS(2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%), and FBXW7 (5%).[30] Whole-genome microarrays of 20 BCCs also found Wnt signaling to be up-regulated in BCC.[29] Comprehensive genomic profiling of 60 patients with 315 genes showed the following additional mutations: CDKN2A (16%), hTERT (33%), ARID1A (18%), NOTCH1 (12%), ERBB2(10%), PIK3CA (8%), BRCA2 (2%), and MLL2 (18%).[31]

A case report showed a CR to pazopanib (a potent VEGFR inhibitor) in a patient with metastatic BCC who was treated after NGS demonstrated the tumor harbored a KDRgene mutation, a gene which encodes VEGFR-2.[65]

Buparlisib (BKM120) is a pan-class 1 PI3K inhibitor currently being studied in clinical trials for a wide variety of cancers. Given the important role for PI3K in the Hedgehog signaling pathway, a pilot study of combination therapy with sonidegib and the PI3-kinase inhibitor buparlisib is currently underway (NCT02303041).

Finally, a recent report demonstrated that PD-L1 amplification, a feature associated with response to checkpoint inhibitors in Hodgkin lymphoma,[51] was found in two of eight patients with advanced basal cell carcinoma and was associated with response to checkpoint inhibitor administration.[55]