Targeted therapy in advanced desmoid tumors: Current perspectives

A normal APC protein prevents the accumulation of beta-catenin, by mediating its phosphorylation and resultant degradation. In APC mutation, either germline or sporadic, premature truncation will lead to loss of the beta-catenin regulatory domain, therefore, beta-catenin is accumulated and subsequently activates the transcription factor-4 (tcf-4), which in turn causes transcription of many genes such as CYCD1 and MYC, leading to proliferation and enhanced survival.[9]

DTs have been reported to occur in 7.5% to 16% of patients with FAP, and the relative risk is much higher than the general population. Although they can occur with mutations in any APC gene location, in some reports, the occurrence of DTs/AF in patients with FAP may be correlated with the specific type and site of mutation.[10] In one study of 36 patients from 20 families with FAP and mutations in codons 1445 to 1578, all developed DTs. In a meta-analysis of many studies of FAP patients, the independent predictors of increased risk of DTs were a positive family history of DT, female sex, and an APC mutation 3’ to codon 1399. [11] A study done by Wallis et al. revealed that the highest risk of developing DTs (100%) exists on the APC mutation in codons 1395– 1493.[12] Another study of 953 FAP patients from 187 families revealed that mutations between codons 1310 and 2011 were associated with a six-fold risk of DTs. [13] The relationship between genotype and phenotype suggests specific roles of the APC protein in different tissues. For example, dental manifestations of Gardener syndrome have been suggested to be associated with mutations at or near codon 1556.[14]

The Wnt/beta-catenin signaling pathway is thought to play a major key in the molecular pathogenesis of DTs, both those associated with FAP and sporadic tumors. The basic features of the Wnt signaling pathway are illustrated in Figure 1.[15]

Figure 1

As discussed before, the levels of beta-catenin in the cell are regulated by phosphorylation, which results in the destruction of beta-catenin in the proteasome. Activation of the Wnt pathway was initiated by the binding of an external ligand causing inhibition of the kinase activity of the APC complex resulting in greater levels of beta-catenin in the cell. Mutations in the beta-catenin gene have been found in sporadic DTs with variable prevalence (39 to 87 %).

In a retrospective study of patients with extra-abdominal DTs, Domont and colleagues reported CTNNB1 mutations in 87% of patients, and the 5-year RFS rate was significantly worse in patients with CTNNB1 mutation, regardless of the genotype, compared with wild-type tumors (49% vs. 75%, respectively).[16]

Three distinct mutations, 41A, 45F, and 45P, were identified with 59%, 33%, and 8% of cases, respectively. Mutation 45F was associated with a high risk of recurrence; 5-year RFS rate was 23% for patients harboring 45F mutation compared to 57% for those with 41A and 68% for those with no mutations, after primary resection,[17] which are matched with the study done by Columbo et al.[18]

In contrast to these findings, Mullen and colleagues reported that CTNNB1 mutation status was not associated with any statistically significant difference in recurrence risk in a subset of 115 patients with DTs who underwent macroscopically complete surgical resection.[19] At a median follow-up of 31 months, the 5-year RFS rates were 58% and 74%, for patients with CTNNB1 mutations and for those with wild-type tumors, respectively.

In fact, there is no agreement on the prognostic significance of different beta-catenin mutations. Additional prospective studies are needed to confirm whether genotyping of CTNNB1 may provide important information about the risk of recurrence and patients’ selection for therapeutic options.

Evidence anticipates that receptor tyrosine kinases (RTKs) such as platelet-derived growth factor receptor, α or β type (PDGFRα or PDGFRβ), epidermal growth factor receptor (EGFR), receptor tyrosine– protein kinase erbB-2 (HER-2), and mast/stem cell growth factor receptor (KIT) are active in DTs/AF. However, it failed to detect correlations between the expression or activation status of these RTKs and responses to receptor tyrosine kinases inhibitors (RTKI).[20,21]

Many chromosomal abnormalities have been described in DTs/AF, especially the occurrence of loss of 6q, 5q, trisomy 8, 20, and monosomy 20. The presence of trisomy 8 and 20 occurs in 25–30% of tumors, and the proportion of cells affected in tumor samples had been reported to vary from 2% to 25%. Till now, the clinical value of these genetic abnormalities is unclear, however, in some reports, their presence has been associated with a higher risk of local recurrence.[22]

There is no consensus on the importance of Ki-67 and p53 in DTs/AF; however, some reports have considered them markers for reduced disease-free survival.[23]

In trying to explain the lack of DTs/AF to metastasize, Bacac et al. revealed that lower expression of osteopontin secreted protein and nodular fasciitis, which might help in understanding their inability to metastasize.[24]

In the Wnt/beta-catenin pathway, the cyclooxygenase-2 gene is triggered; this gene’s activity contributes to tumorigenesis by inhibiting apoptosis, stimulating angiogenesis and invasiveness, and modulating cell proliferation by increasing the expression of growth factors such as PDGFs.[25] Many studies have proved that DTs/AF had a high estrogen level (ER), but negative for progesterone receptor (PR). This information suggests that they may grow under hormonal control and can possibly be influenced by hormonal manipulations.[26]

Imatinib mesylate is a small-molecule TKI that was initially developed as a 2-phenylaminopyrimidine derivative specific to PDGFR. It was subsequently found to be a potent inhibitor of ABL kinases and was also found to inhibit the RTK and KIT. Mace and colleagues revealed objective remissions and disease stabilization in two patients with unresectable and progressive DTs/ AF when treated by imatinib.[28]

In phase II clinical study, 84% of patients had mutations involving the Wnt pathway (APC or CTNNB1), imatinib was used in a dose 800 mg/day to treat patients with advanced DTs/AF. The results revealed partial response (PR) and stable disease (SD) in 15.7% and 21% of patients, respectively.[29] Similar observations have been reported by Chugh et al.[30]

Long term follow up results of phase II study done by the French Sarcoma Group also showed that at 3 months, 3% of patients achieved complete response (CR) and 9% PR in patients with recurrent or progressive DTs/AF. At a median follow up of 34 months, the non-progression rates at 3, 6, and 12 months were, respectively, 91%, 80%, and 67%. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 55% (95% CI 39–69) and 95% (95% CI 82–99), respectively. Imatinib toxicity was similar to that previously reported in the literature.[31]

Sorafenib (BAY-43–9006) is a multi-targeted oral TKI, inhibiting KIT, PDGFR, and VEGFR. In a retrospective cohort, Gounder et al reviewed the data for 26 patients with DTs treated with 400 mg oral daily sorafenib with dose adjustment. The median dose was 200 mg/ day. Some patients required dose modifications to 200 mg every other day, meanwhile others tolerated alternating doses of 400 mg and 200 mg daily (300 mg/day). Sorafenib was the first-line therapy in 11 patients and subsequent therapy in 15 patients after a median of 2 prior lines of therapy. The previous systemic treatment included hormonal manipulation, TKIs, and chemotherapy. 88.5% of patients had shown evidence of progressive disease, whereas 11.5% of patients had achieved maximum benefit. At a median of 6 months of treatment, 25% of patients exhibited PR, 70% with SD, and 5% with progression and death. There was a statistically significant radiological benefit in extremity DTs/DF rather than intra-abdominal tumors (p = 0.03).[32]

Sunitinib malate is a multi-targeted TKI with activity against VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, KIT, and FLT3. In a prospective multicenter phase II study that included 19 patients with advanced DTs/AF showed that the OS rate was 26.3%. With a median follow-up time of 20.3 months, the 2-year rates of PFS and OS were 74.7% and 94.4%, respectively. According to this result, sunitinib is considered as an option in advanced DTs/AF. A prospective multicenter phase II trial included 19 patients with DTs/AF to evaluate the safety and efficacy of sunitinib. The treatment plan consisted of 3 weeks on and one week off (37.5 mg/ day sunitinib). The tumor RR was the primary endpoint based on RECIST 1.0. The results showed that the ORR was 26.3% (95% CI, 6.3–45.7) and the disease control rate was 68.4% (95% CI, 47.5–89.3). The 2-year rates of PFS and OS were 74.7% and 94.4%, respectively. Grade 3 or 4 AEs reported in more than 5% of patients were neutropenia (33.3%), hand-foot syndrome (5.3%), and diarrhea (5.3%). Of the 12 patients with mesenteric DTs/AF, only 3 patients developed surgical complications (bowel fistula [n = 1], bowel perforation [n = 1], mesenteric mass bleeding [n = 1]). The authors concluded that sunitinib had a potential antitumor activity with an acceptable side effect.[33]

In a case study done by Scheer et al., addressed that the sunitinib achieved PR after multiple lines of systemic chemotherapy in young women with DTs/AF in breast cancer.[34] Moreover, the same results were reported by Skubitz et al. in another case report study.[35]

Pazopanib is a multi-tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, (PDGFR)-α, and KIT. It has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of advanced renal cancer and soft-tissue sarcomas (STS).

In two different institutions, two patients with progressive DTs/AF were treated with pazopanib showed marked clinical improvement lasted for more than one year, with better and tolerable toxicity than conventional chemotherapy.[36]

A multicenter randomized non-comparative phase II study was conducted to evaluate the safety and efficacy of pazopanib compared to methotrexate/vinblastine (MV) in patients with DTs. The results showed that in the pazopanib arm, the PR was detected in 37% of patients and SD in 45.7%. While in MV-arm, the PR in 25% and SD in 30%. The 6-month non-PD rate was 86% (95% CI = 72.1–94.7) in pazopanib arm and 50% (95% CI = 27.2–72.8) in MV-arm.[37]

B-secretase is a membrane-anchored aspartyl protease in the pepsin family, while γ-secretase is an unusual protease with highly promiscuous through the transmembrane domain of its substrates. PF-03084014 is a γ-secretase inhibitor evaluated in patients with refractory, recurrent, progressive DTs/ AF. A prospective study evaluated PF-03084014 on 17 patients with recurrent or refractory DTs/AF. The treatment plan consisted of PF-03084014 150 mg orally twice a day in 3-week cycles. the evaluation was at cycle one and every 6 cycles. The primary endpoint was objective RR. The mutations either germline or somatic in APC and CTNNB1 were genotyped in blood samples and archival tumor. The results revealed that 88% of patients had mutations in CTNNB1 or APC genes. 29 % had PR, and another 29% experienced SD. Patients reported that the drug is tolerable. In conclusion, the investigators reported that PF-03084014 had a promising clinical activity with a tolerable side effect.[38]