Abstract
Recent advances in our understanding of the molecular biology of salivary gland neoplasms have yielded diagnostic targets and potential therapeutic targets that have started to change our approach and choice of treatment strategies. Currently, these options are mainly investigated in recurrent and metastatic salivary gland cancer (SGC). Although the results of both cytotoxic and targeted molecular biological systemic therapy for locoregional recurrence and distant spread of SGC remain largely unpredictable, targeted therapy can be the treatment of choice in selected cases today. Molecular analysis is required as part of the diagnostic workup to help select patients with recurrent and metastatic SGC who may benefit from targeted or standard treatment regimens.
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Introduction
The annual incidence of salivary gland carcinomas ranges from 4 to 135 new patients per 106 people, with the highest incidence rates reported in Greenland and the Canadian Arctic [1]. The US incidence is reported as 10 new patients per 106 per year [2], and somewhat lower European incidences, such as reported in Finland, Belgium, The Netherlands and the UK, amount to about 6–7 per 106 per year [3–6]. The major salivary glands give rise to 90–95 % of these tumors, where 70 % occur in the parotid and 20–25 % in the submandibular and sublingual glands. Less than 10 % arise in the minor salivary glands [3, 4, 7–9].
This review focuses on recent advances in our understanding of the molecular biology of these rare cancers and aims at updating the reported experience with cytotoxic and targeted molecular biological agents in the recurrent—metastatic disease setting.
Diagnosis: Histotyping and Grading
In 2005, the World Health Organization (WHO) published the current reference classification featuring 24 different types of salivary gland cancer (SGC) [10]. The pathologist combines light microscopic features and immunohistochemistry to (1) assign a specific tumor to one of the categories in this classification (histotyping); (2) describe negative prognostic features (lymphovascular invasion, positive resection margins, perineural growth, etc.); and (3) for specific subtypes, to grade the tumor. Molecular markers are becoming increasingly important in the diagnostic fine-tuning of SGCs.
Histotyping
There is frequently no uniform relationship between histotype and biological behavior [11]. Only population-based studies give a true reflection of the distribution of the 24 histotypes. In such population-based studies, the majority of major SGCs are acinic cell carcinoma (AcCC: 15–17 %), adenoid cystic carcinoma (AdCC: 16–27 %), and mucoepidermoid carcinoma (MEC: 14.5–19 %) [6, 12]. In most studies of minor SGCs, AdCC and MEC account for up to 89 % of histologic types, and AdCC (32–71 %) and MEC (15–38 %) far outnumber adenocarcinoma Not Otherwise Specified (ACNOS), AcCC, polymorphous low grade adenocarcinoma (PLGA), epithelial myoepithelial carcinoma, and carcinoma ex-pleomorphic adenoma (CXPA) [9]. Histotyping of SGCs is challenging, and marked by high reclassification rates following slide review of historical series. Examples are the 29 % reclassification rate resulting from application of a new histologic classification system as reported by van der Wal et al. [13] and a 22 % reclassification rate as reported in our own series [14]. A substantial interobserver variability between pathologists also exists [15]. Reclassification, interobserver variability, geographic variation and referral bias all contribute to disparities in the published histology distribution. For clinical purposes, we routinely divide the different histotypes into clinically low-grade (AcCC, PLGA and low-grade MEC), intermediate-grade (epithelial myoepithelial carcinoma and AdCC) and high-grade carcinomas (salivary duct carcinoma—SDC, ACNOS, high-grade MEC, CXPA and undifferentiated carcinoma). However, also the clinical grade assignment does not always parallel clinical behavior. This “clinical grading” has to be distinguished from the “histopathological” or “optical” grading described in the next paragraph.
Histopathological Grading
Optical grading by the pathologist is an attempt to explain variable biological behavior within tumors of the same histotype and is well established in the three most frequent salivary gland carcinomas: MEC [15–17], AcCC [18] and AdCC [19, 20]. However, grading shows poor inter- and intraexaminer consistency with a low independent prognostic power in multivariate analysis, because grading parallels other important prognostic factors that are more reliable to reproduce such as age, stage, perineural growth and irradical surgery [8].
Molecular Biology in Diagnosis and Prognosis
Molecular markers are a main focus of current salivary gland tumor research. As optical grading suffers from interobserver variation and is collinear with many other strong clinicopathological factors, molecular markers are being investigated for their potential prognostic role and may prove more reliable in predicting outcome. They are also under study as therapeutic targets.
Cell Cycle-Based Proliferation Markers
The endpoint of the accumulation of genetic and epigenetic changes that leads to deranged growth is reflected by the expression of cell cycle-based proliferation markers. Their expression parallels the number of cells going through the cell cycle toward division. Among cell-cycle based proliferation markers in SGC, well studied are the expressions of Ki-67, an anti-apoptotic nuclear antigen in proliferating cells [21–23], proliferating cell nuclear antigen (PCNA, a co-factor of DNA polymerase) [24, 25], human telomerase reverse transcriptase (hTERT) [26] and AgNOR (argyrophylic nucleolar organizer region-associated proteins) [27, 28], as well as TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling] assays that identify DNA breaks in apoptotic cells [29]. The most widely used of these is the general overall proliferation marker Ki-67, which is widely applicable and correlates well with biological behavior [21]. Together with age and tumor stage, the Ki-67 index is an important and independent prognostic factor on multivariate analysis, irrespective of tumor subtyping, grading or morphological appearance of the salivary gland tumor [30 ••].
Separately Studied Genetic and Epigenetic Changes
At the basis of the deranged growth (that is reflected by the cell cycle-based proliferation markers just mentioned) is an accumulation of genetic and epigenetic changes, which are all elements of the cascade that ultimately results in uncontrolled growth. Many of these elements have been studied separately, but the prognostic value can be confirmed only if they remain independent on multivariate analyses. Some of these markers have also been investigated as therapeutic targets, and these are tabulated in Table 1 [31–43]. For the description of these markers, we grouped them using a similar structure as in our previous review paper on parotid carcinoma [8].
Growth Factor Receptor Proteins and Their Ligands
Stem cell factor receptor (c-KIT, a transmembrane tyrosine kinase), angiogenesis-related growth factor receptors (VEGF-R, PDGF-R, bFGF-R, IL-8, PlGF, TGFβ, EphA2), nerve growth factor (NGF), the ErbB/HER family of human epidermal growth factor receptors (EGFR also named HER-1 or ErbB-1; HER-2 or HER2/Neu or ErbB-2; HER-3 or ErbB-3; HER-4 or ErbB-4), insulin-like growth factors (IGF–I/II) and receptor (IGF-1R) and receptor tyrosine kinase MET and its ligand hepatocyte growth factor can be put in this category.
c-KIT is detected in 80–94 % of AdCC [44] and in 100 % of lymphoepithelial-like salivary gland carcinomas and myoepithelial carcinomas, and in a subset of other tumors as well [44]. In AdCC, the relation between high c-KIT expression (>50 %) and grade has been widely discussed and remains unresolved. In one study this feature was significantly more common in grade 3 or solid-type AdCC [45], but Freier et al. [46] found the opposite: high expression only in cribriform and tubular AdCC.
For angiogenesis-related growth factor receptors, Lim et al. [47] describe the prognostic value for VEGF expression, which is found in many SGCs. In multivariate analyses, VEGF expression was associated with advanced stage and worse DSS [48]. Greater expression of EphA2, a receptor tyrosine kinase involved in angiogenesis, and its ligand ephrin A1 has recently been described in AdCC, where expression correlates to microvessel density, TNM stage, perineural invasion and vascular invasion. This expression is significantly greater in solid type AdCC than in the cribriform and tubular types [49].
In the human epidermal growth factor receptor family, EGFR identification and overexpression correlate with aggressiveness in MEC [50], SDC [51, 52] and AdCC [50, 51]. Although EGFR protein expression is common in SGC, it is not associated with gene amplification [53]. Activating mutations of EGFR are rare in SGC, but when present, they may be linked to good response to anti-EGFR therapy in a way similar to what is observed in non-small cell lung cancer [53]. A recent study by Lee et al. [54] was not able to link the expression of EGFR, c-KIT and VEGF to prognosis in AdCC. HER-2 has been found overexpressed in AdCC, SDC [52, 55, 56], CXPA [57] and about 30 % of MEC [25, 38, 50, 58, 59]. Furthermore, it is a negative prognostic marker in multivariate analysis, independent of histopathological grade, tumor size and involvement of regional lymph nodes [59]. Aggressively behaving AdCCs also display HER-3 expression [50].
Increased expression of NGF, besides increased VEGF expression, has been described in AdCC, possibly accounting for its neurotropism [60]. In the same line, recently Ivanov et al. [61 ••] observed overexpression of a large cluster of neuronal genes grouped around TrkC/NTRK3, a tyrosine kinase neurotrophic receptor associated with neurogenesis and cancer, in AdCC. This finding suggests that AdCC aberrantly expresses genes involved in neural stem cell differentiation.
The receptor tyrosine kinase MET and its ligand, the hepatocyte growth factor, activate different cellular signaling pathways leading to tumor cell proliferation, migration, motility and invasion. In SGC, aberrations of genomic MET are associated with lymphatic spread and are characteristic for high-risk tumors with poor overall survival [62 •]. Multivariate analysis showed that aberration of MET is a very strong predictor of lymph node metastasis, even stronger than the established criteria of tumor size and grade [63].
Cell Cycle Oncogenes
The above-mentioned growth factor-receptor interaction activates cell cycle oncogenes, including sex-determining region Y-box 4 and 10 (SOX-4, SOX-10), nuclear factor κB (NFκB) [64, 65], human rat sarcoma viral oncogene homolog (H-RAS), phosphatidylinositol 3 phosphate kinase/serine-threonine protein kinase Akt (PI3 K/AKT) [65], sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (Src), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin [mTOR, activated by AKT, regulating protein synthesis depending on nutrient availability and negatively regulated by the tumor suppressor gene phosphatase and tensin homolog (PTEN)], peroxisome proliferator-activated receptor gamma (PPARγ) [66] and cyclin D1.
In a large microarray analysis of AdCC, Frierson et al. [67] found that SOX-4 was the most significantly overexpressed cell cycle oncogene. Furthermore, increased apoptosis following SOX-4 knockdown suggests that this oncogene exerts its activity via downregulation of inhibitors of the NFκB pathway (inhibitor protein I-κB-α) and by upregulation of apoptosis inhibitors such as survivin [68]. More recently, the transcriptional factor SOX-10, normally only expressed during salivary gland differentiation, was found markedly upregulated in a great majority of AdCC cells [69]. Mutations of H-RAS are observed in CXPA [70], ACNOS [71] and almost half of MECs, where the frequency of H-RAS mutations parallels tumor grade [72]. Cyclin D1 seems frequently overexpressed in AdCC and MEC and correlates to prognosis [73, 74]. In MEC, high cyclin D1 expression follows inactivation of secreted frizzled-related proteins (SFRPs) by hypermethylation [74]. Nuclear STAT3 expression seems to play a role as a tumor suppressor in the absence of EGFR, HER-2 and survivin in SGC [52]. RUNX3, a tumor suppressor gene that, when active, facilitates TGF-beta to play its apoptotic role, appears silenced by hypermethylation in AdCC [75]. Expression of PDCD4 (programmed cell death 4), a recently described tumor suppressor gene inhibiting neoplastic transformation and tumor promotion/progression, is downregulated in the majority of AdCCs. Decreased PDCD4 expression is also significantly associated with the clinical stage of the disease and poor prognosis. Multivariate analysis demonstrated that PDCD4 expression is an independent risk factor for AdCC [76 •]. Suprabasin (SBSN), a novel oncogene in AdCC, plays important roles in maintaining cell proliferation and invasive metastatic capability in AdCC. Moreover, the expression of SBSN is upregulated by CpG island demethylation, and hypomethylation of SBSN is significantly more frequent in AdCC than in normal salivary gland tissues [77]. RB1-inducible coiled-coil 1 (RB1CC1) is a positive regulator for the retinoblastoma tumor suppressor (RB1) pathway, and its expression in SGCs appears to imply better prognosis, analogous to what has been shown for breast cancer [78]. Expression of ERBB3-binding protein 1 (EBP1), a molecule with multiple roles in cell proliferation and differentiation, was found to be inversely correlated with local invasion and distant spread of AdCC. Patients with lower EBP1 levels had poorer long-term survival than those with higher EBP1 expression, and this follows the upregulation of E-cadherin by EBP1, inhibiting the migration and invasiveness of AdCC [79]. The PI3K/AKT/mTOR (mammalian target of rapamycin) axis plays a critical role in tumorigenesis. Dysregulation of this molecular pathway involves alterations of AKT, mTOR, PTEN and various upstream tumor-associated growth factors (EGFR, HER-2, PDGF and VEGF) [80]. Loss of PTEN goes along with stimulation of the PI3K pathway, promoting cell survival and tumor growth, resulting in cell migration and metastasis by deregulation of cell interactions with the extracellular matrix. Loss of PTEN has been described in a subset of highly malignant SGCs and was assocciated with high levels of EGFR and HER2 [81 •]. Recently, deletion of PTEN was found a strong predictor of neck node metastasis, remaining so in multivariate analysis [63]. Efforts are underway at targeting the PI3K/AKT pathway by blocking mTOR with temsirolimus [82].
Pleomorphic adenoma gene 1 (PLAG1) is a specific proto-oncogene found in a large percentage of pleomorphic adenomas and is transcribed and overexpressed following a t(3;8)(p21;q12) chromosome translocation resulting in β-catenin-promoter swapping. This causes deregulated expression of PLAG1 target genes by the IGF-II IGFIR mitogenic signaling pathway [83]. Another fusion oncogene, MEC translocated 1 gene with exons 2–5 of the mastermind-like gene 2(MECT1-MAML2); t(11;19)(q14–21;p12–13) [84] is transcribed into a fusion protein that was initially thought to be exclusively seen in low-grade MEC histology [85, 86]. However, high-grade fusion-positive MECs associated with advanced-stage lethal disease have now been described [87]. For AdCC, a recurrent reciprocal translocation of t(6;9)(q22–23; p23–24) resulting in fusion gene partners comprising the MYB gene and the transcription factor NFIB (previously reported in AdCC of the breast, lacrimal and ceruminal glands) has now been described. In both fusion-positive and a subset of fusion-negative AdCCs, high expression of the transcript Myb was found, suggesting this as a potential target for new therapies [88].
Proteins Involved in DNA Damage Repair
p53 and ERCC1 (excision repair cross-complementation group 1) belong in this category. p53 expression [89] and p53 mutations in AdCC are generally associated with worse outcome [90], but a large Finnish multivariate analysis failed to confirm this information as having additional value over a classical clinicopathological multivariate model. This large study however did not focus on the AdCC subgroup but studied all SGC types [91].
Proteins Involved in Apoptosis
The Bcl-2 group contains pro-apoptotic proteins such as Bax, Bad and Bak and anti-apoptotic proteins such as Bcl-2, Bcl-xL and survivin. High Bcl-2 expression in SGC relates to poor prognosis and advanced T and N classification [92]. Nuclear survivin expression indicates aggressive SGC with worse prognosis [52].
Proteins involved in cell-cell adhesion (hemidesmosome proteins B180 and B230, E- and N-cadherin, CDH12, α-catenin, mammalian ENA, CD44 and CD24) [93–98], migration (matrix metalloproteinase, heparanase, CD147 or extracellular matrix metalloproteinase inducer or Emmprin) [11, 99–102] and epithelial-mesenchymal transition (NBS-1 and snail)
Matrix metalloproteinase 9 (MMP-9) degrades type IV collagen, a major component of basement membranes in human tissues, and allows the tumor cells to break through the site of the primary tumor, leading to invasion and metastasis. MMP-9 was recently found to be overexpressed in SDC, together with tumor cell-associated extracellular MMP inducer, CD147, which regulates the expression level and activity of MMP-9 and MMP-2. High expression of CD147 and MMP-9 was significantly correlated with invasion, metastasis, shorter progression-free survival and shorter overall survival (poor prognosis) compared with SDC patients with low CD147/MMP-9 expression [102]. Recent research identified an association between ILK (integrin linked kinase) and epithelial-mesenchymal transition markers in adenoid cystic carcinoma (AdCC). ILK plays a key role in cell-extracellular matrix interactions, regulating cell proliferation, apoptosis, differentiation and migration. Positive expression of ILK correlates strongly with solid-type AdCC, advanced TNM stage and increased risk of recurrence. Moreover, upregulation of Snail and N-cadherin and downregulation of E-cadherin correlated significantly with ILK overexpression and a neural invasive phenotype. Through epithelial-mesenchymal transition by upregulation of Snail, downregulation of E-cadherin and upregulation of N-cadherin, ILKs may have an important role in progression and metastasis in AdCC [103].
Estrogen, Progesterone and Androgen Receptors [51, 66, 104 ••]
Estrogen receptors have been described in AdCC, whereas androgen receptors have been the target of hormonal therapy in SDC. In a study that examined 139 cases of SGC, androgen receptor expression was found in 13 %, but no expression of estrogen or progesterone receptor was detected [105•].
Markers for Lymphangiogenesis
Podoplanin (T1a-2, aggrus or gp36) is a small mucin-like protein and its function is related to tissue development and repair. It is specifically expressed in lymphatic endothelial cells and is used as a specific marker for lymphangiogenesis. It is also expressed in certain tumor cells and is associated with migration/invasion in cervix and oral squamous cell carcinoma. Recently, Podoplanin was found to be overexpressed in a subset of salivary gland AdCCs (32.5 % of tumors). Overexpression was significantly associated with disease-free survival and distant metastasis, although it was not associated with recurrence and overall survival [106].
Viral Etiology
Recently the interesting hypothesis was put forward that the hCMV virus is implied in the oncogenesis of MEC. This awaits further validation in larger series, but the authors found the viral protein expressed in almost all cases studied [107 •].
Transcription Factors
In AdCC, significant epigenetic changes (hypermethylation) were observed at the transcriptional start sites of genes that encode for the transcription factor Engrailed homeobox 1 (EN1), which plays an important role in the development of the central nervous system. Hypermethylation of EN1 correlates with histologic tumor grade, tumor location and final patient outcome in AdCC [108]. Moreover, EN1 protein expression was typical for solid type AdCC and implied a significantly lower survival rate, making EN1 a potential biomarker in AdCC [109].
Treatment with Cytotoxic Chemotherapy in the Palliative Setting
In advanced SGC, no standard systemic treatment is available. Cytotoxic chemotherapy is generally used in the context of a palliative therapy, based on level 3 evidence (case-control or cohort studies). The data supporting the use of chemotherapy are scarce, because trials involve small populations with important heterogeneity regarding the histology, prior systemic therapies and proportion of patients with locoregional recurrence versus distant metastasis. Moreover, the majority of SGCs have a slow growth pattern, making it difficult to assess the response of the tumor to chemotherapy.
Monotherapy (Single-Agent Chemotherapy)
Cisplatin is the most extensively studied single-agent chemotherapy for advanced SGC. The largest phase II study included 25 patients with AdCC, MEC and ACNOS and showed a mean response rate of 18 %, response duration between 5 and 9 months, and a median overall survival time of 14 months [110]. On the other hand, De Haan et al. [111], including ten patients with advanced AdCC, observed no objective responses: five patients showed stabilization of their disease for a median duration of 20 months.
In AdCC, mitoxantrone, epirubicin and vinorelbin all appear to have activity as a single agent. In a study including 32 AdCC patients, mitoxantrone induced a partial response in four patients, lasting from 3 to 13 months, and 22 patients had stable disease [112]. Although treatment with epirubicin yielded a rapid improvement in disease-related symptoms in 29 % of patients in a phase II trial including 20 patients with advanced or recurrent AdCC, the response rate remained low (10 %) and the median time to disease progression short (16 weeks) [113]. Vinorelbin has moderate activity in AdCC and ACNOS with overall response rates of 20 %, median partial response duration of 6 months, median time to disease progression of 5 months, median stable disease duration of 3.5 months and median overall survival of 8.5 months [114]. In a study by Gilbert et al., paclitaxel did not show any activity in AdCC, but it appears to provide some objective responses in MEC and ACNOS [115]. Gemcitabine monotherapy showed no objective responses in AdCC [116].
Combination Therapy
The most studied regimen in the treatment of advanced SGC is CAP (cyclophosphamide, doxorubicin and cisplatin) [117]. A phase II trial by Licitra et al. [118], treating 22 patients with advanced SGC (AdCC and non-AdCC), achieved partial responses in only six patients, with an overall response rate of 27 %. In our patients with metastatic ACNOS treated with CAP, we observed a 60 % response rate, but the responses were generally short-lived with a median time to progression of 6.6 months [119].
Tsukuda et al. [120] documented a 36 % response in 14 patients with ACNOS or AdCC treated with CPPr (cyclophosphamide, cisplatin and pirabucin, a less cardiotoxic anthracycline analog). In a series of 17 patients treated with PAF (cisplatin, doxorubicin and 5-fluorouracil), overall response was 35 % (12 % complete, 23 % partial response), with response duration of 6 up to 15 months but no survival advantage [121]. A combination treatment of cisplatin, epirubicin and 5-fluorouracil (PEF) did not do better than cisplatin monotherapy (one partial response out of eight patients) [122]. Evaluating FACP (5-fluorouracil, doxorubicin, cyclophosphamide and cisplatin) in 17 patients with advanced SGC, the objective response rate was 50 % (44 % partial, 6 % complete response) with a median duration of 7 months, but with a higher toxicity than three-agent regimens [123]. A small randomized study compared vinorelbine with a combination of vinorelbine-cisplatin (PV) in 16 patients with recurrent SGC of all three major histologic subtypes. Overall response of the PV regimen was 44 %. Median duration of complete response was 15 months and of partial response 7.5 months, making PV better than vinorelbine in monotherapy. Compared to CAP, PV could be less toxic and equally effective [114]. A combination of carboplatin and paclitaxel only achieved two partial responses in 14 patients with SGC, resulting in a median survival of 12.5 months [124].
More recently, Laurie et al. evaluated a gemcitabine-cisplatin/carboplatin (GP) regimen in 33 patients with advanced SGC. The response rate was 24 %, median response duration 6.7 months. Thus, GP demonstrates modest activity in advanced SGC but no advantage over other cisplatin-based regimens (e.g., CAP) [125].
In conclusion, whether or not combination chemotherapy is better than monotherapy for SGC is still uncertain. Combination regimens generally result in higher response rates at the cost of additional toxicity, but fail to improve survival [126]. A recent high-quality meta-analysis focusing on locally recurrent or metastatic AdCC reaches the same conclusion [127••]. This study evaluated the activity of combination chemotherapy in 143 patients enrolled in 17 trials. In 14 studies, cisplatin-based regimens led to objective responses in 29 of 118 patients (response rate 25 %). Response duration ranged widely, from 6 to 77 months.
Treatment with Cytotoxic Chemotherapy in the Curative Setting
Treatment with Targeted Therapies
The explored targeted therapies are listed in Table 1.
Imatinib
Although c-KIT is overexpressed in up to 94 % of AdCCs, results of treatment with imatinib (c-KIT tyrosine kinase inhibitor) are disappointing. Imatinib as a single agent was evaluated in 5 studies including 54 patients [31, 32, 34, 42, 130]. Stable disease was observed in 19 patients (35 %). Only two objective responses were reported (3.7 %), both in a study requiring progressive disease and high c-KIT expression for inclusion [42]. One phase II study, evaluating the combination imatinib/cisplatin in 28 patients with locally advanced and metastatic AdCC, showed a partial response in 3 of 28 patients, while 19 patients (68 %) had disease stabilization [131].
Lapatinib
Lapatinib, a dual inhibitor of EGFR and HER-2 tyrosine kinase activity, was evaluated in 40 patients with progressive metastatic or recurrent SGC with proven EGFR/HER-2 overexpression. Although no objective responses were seen, disease stabilization for at least 6 months was observed in 13 patients (32.5 %). Because disease progression was needed to meet the inclusion criteria, the disease stabilization was likely due to the effect of lapatinib [33].
Gefitinib
Despite the common EGFR expression in SGC, the orally active EGFR tyrosine kinase inhibitor gefitinib performs poorly in patients with advanced SGC. A phase II study including 28 patients with advanced SGC reported no objective responses and stable disease in 14 patients, with a median duration of 3 months. Of the latter, 13 patients had AdCC, typically behaving in an indolent way, making “stable disease” an unreliable endpoint [132].
Bortezomib
Bortezomib inhibits the proteasome that normally degrades the NFκB inhibitor (I-κB-α). In this way, NFκB, related to angiogenesis and poor patient outcome, is inhibited. Bortezomib was tested in a phase II trial including 24 patients with recurrent or metastatic AdCC, but no objective responses were observed. Fifteen of 21 evaluable patients (71 %) showed disease stabilization for a median duration of 4.2 months and an overall survival of 21 months. In ten patients, doxorubicin was added at disease progression, leading to one partial response and five disease stabilizations (median duration, 5.2 months) [41].
Sunitinib
The antitumor activity of sunitinib, a multitarget inhibitor of VEGF-R, PDGF-R, c-KIT, ret proto-oncogene (RET) and FMS-like tyrosine kinase 3 (FLT3), was assessed in a phase II study. In 13 patients with recurrent and/or metastatic AdCC, no objective responses were seen, and 11 patients showed stable disease, in 8 patients stable for minimally 6 months. Median time to progression was 7.2 months, while median overall survival was 18.7 months [133].
Cetuximab
The anti-EGFR monoclonal antibody cetuximab was evaluated in a phase II trial including 30 patients with advanced SGC [37]. No objective responses were reported, but stable disease was recorded in 24 (80 %) patients, lasting for more than 6 months in 15 of them. Molecular analysis showed no EGFR gene amplification, and just 12 % of AdCCs showed an increase in the EGFR gene copy number. Clauditz et al. confirm this finding that, although EGFR protein expression is common in SGC, EGFR gene amplification and activating mutations are rare. Several studies, e.g., in non-small cell lung cancer, suggest a predictive role of the EGFR copy number for anti-EGFR therapy response, so selected cases of patients with advanced SGC and an increased EGFR copy number might derive more benefit from anti-EGFR therapy [53].
Trastuzumab
Trastuzumab, a monoclonal antibody interfering with the HER-2 receptor, was tested for the first time in a phase II trial by Haddad et al. in advanced SGC overexpressing HER-2. The study closed early because of the low rate of HER-2 overexpression in the SGC screened for study entry. One objective partial response in a patient with MEC lasted for more than 2 years, but the rest showed disease progression after a median time of 4.2 months, so the conclusion was that trastuzumab is not active in advanced SGC [39]. Nabili et al. [40] reported one complete response in three patients treated with trastuzumab for progressive SDC. Limaye et al. [43] recently retrospectively assessed trastuzumab combined with paclitaxel and carboplatin in an adjuvant or palliative setting in 13 patients with HER-2 positive SDC. All patients with metastatic disease (5 patients) responded for a median duration of 18 months; one patient achieving a complete response remained free of disease 52 months after initiation of therapy.
Conclusion
Recent advances in our understanding of the molecular biology of SGC have yielded diagnostic targets and also potential therapeutic targets for patients with locally recurrent or metastatic disease, but to date, the results of systemic treatment by means of cytotoxic chemotherapy or targeted molecular therapies remain modest. At best, temporary, usually partial, disease response or stabilization can be achieved before disease progression occurs. Multi-institutional and international collaborative efforts to collect and share tumor samples through tissue banks will be necessary to provide the tissue material needed for assessment and validation of diagnostic and prognostic molecular biological advances and to perform multicenter trials of potentially promising new treatment strategies.
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Vander Poorten, V., Meulemans, J., Delaere, P. et al. Molecular Markers and Chemotherapy for Advanced Salivary Cancer. Curr Otorhinolaryngol Rep 2, 85–96 (2014). https://doi.org/10.1007/s40136-014-0040-2
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DOI: https://doi.org/10.1007/s40136-014-0040-2