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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 554-563

Molecular tumor board: Case 4 Salivary Gland Cancer: Novel therapeutic options as a result of comprehensive molecular profiling

1 Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, India
2 Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, India
3 Department of Pathology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, India
4 Tata Memorial Center, Homi Bhabha National Institute (HBNI), Tata Memorial Hospital, Mumbai, India

Date of Submission28-Jul-2020
Date of Decision31-Jul-2020
Date of Acceptance19-Aug-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_258_20

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How to cite this article:
Kapoor A, Noronha V, Chougule A, Chandrani P, Shetty O, Patil VM, Joshi A, Menon N, Bal M, Vaish R, Kumar A, Prabhash K. Molecular tumor board: Case 4 Salivary Gland Cancer: Novel therapeutic options as a result of comprehensive molecular profiling. Cancer Res Stat Treat 2020;3:554-63

How to cite this URL:
Kapoor A, Noronha V, Chougule A, Chandrani P, Shetty O, Patil VM, Joshi A, Menon N, Bal M, Vaish R, Kumar A, Prabhash K. Molecular tumor board: Case 4 Salivary Gland Cancer: Novel therapeutic options as a result of comprehensive molecular profiling. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Sep 25];3:554-63. Available from: https://www.crstonline.com/text.asp?2020/3/3/554/295505

  History, Examination and Radiology Top

A 51-year-old gentleman with no comorbidities or family history presented to our hospital with a deviation of the left side of the face and a swelling in the left parotid region that had persisted for the past 5 months. On examination, there were signs of lower-motor-neuron-type facial nerve palsy with a large hard swelling involving the left parotid region, in the left infra-auricular and postauricular regions with enlarged left level Ib/II nodes. Magnetic resonance imaging (MRI) of the head and neck region was suggestive of an ill-defined hypointense lesion on the T2-weighted image (T2WI), measuring 5.4 cm × 5.1 cm × 4.9 cm and involving both, the superficial and the deep lobes of the left parotid gland completely, with widening of the left stylomandibular foramen and perineural spread along the facial nerve [Figure 1]. The left paraspinal muscle was involved by the tumor. Multiple enlarged metastatic nodes were seen in the left retropharyngeal; levels II, III, IV, V; supraclavicular; and retroauricular regions. The largest node at the left level II measured 2.3 cm × 2 cm. The left internal jugular vein was encased and compressed by the nodal mass up to the jugular foramen. The disease was deemed unresectable due to the involvement of the paraspinal muscles.
Figure 1: Magnetic resonance imaging showing hypointense lesion on the T2 weighted image involving both the superficial and the deep lobes of the left parotid gland completely (a) and multiple enlarged metastatic nodes in the left retropharyngeal, levels II, III, IV, V, supraclavicular and retroauricular region (b)

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  Biopsy and Additional Testing Top

A core biopsy from the parotid swelling was suggestive of a high-grade salivary duct carcinoma, not otherwise specified. On immunohistochemistry, the tumor cells were found to be positive for cytokeratin 7 (CK7) and the androgen receptor (AR); about 90% of the cells showed a strong positive staining for AR [Figure 2], but were negative for p63 and S100P. The tumor nuclei were positive for mismatch repair proteins (MMR): MSH2, MSH6, MLH1 and PMS2. Thus, the tumor was MMR-proficient (negative for microsatellite instability). HER2 cells also stained positively for MSH2, MSH6, MLH1, and PMS2. Additionally, the tumor was found to be HER2-negative by immunohistochemistry (IHC).
Figure 2: Histology of salivary duct carcinoma: (a) Intraductal carcinoma component; (b) invasive carcinoma component displaying malignant glands; (c) tumor cells exhibiting strong and diffuse nuclear androgen receptor immunoreactivity

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  Molecular Testing and Treatment Planning Top

In view of the strong AR-positivity, the patient was started on leuprolide and bicalutamide [Figure 3] shows the important timelines in the case history of our patient]. There was initial improvement in terms of reduced pain and heaviness. However, 3 months after starting the therapy, the patient developed increasing pain and swelling along with occasional post auricular bleeding. A scan also revealed a significant increase in the size of the swelling. He was, therefore, started on weekly paclitaxel and carboplatin. His biopsied tissue was analyzed by next-generation sequencing (NGS). The Ampliseq for Illumina Focus Panel, a targeted gene panel for solid tumors, was used for the detection of single nucleotide variants (SNVs) and insertions and deletions (indels) from 269 amplicons for 41 genes and gene fusions from 284 amplicons for 24 genes. The NGS data had a mean coverage of ×4000, with a quality (Q30) value of 95%; the data were analyzed using the integrative genomics viewer, BaseSpace, and Local Run Manager, Illumina. The BRAFV600E mutation was detected and was classified based on the recommendations of the Association of Molecular Pathology (AMP) guidelines as a Tier I (pathogenic) mutation. Dabrafenib and trametinib were applied for procurement on a compassionate basis (as these medications were not available in India at the time). Meanwhile, the patient was continued on weekly paclitaxel and carboplatin chemotherapy. An MRI after 12 weeks of starting chemotherapy showed a partial response (PR) with significant reduction in the size of the parotid lesion and the nodes. After 17 weeks of paclitaxel and carboplatin chemotherapy, the patient developed grade 1 peripheral neuropathy and grade 2 anemia and neutropenia. Considering the toxicities, the patient was given a treatment break, and meanwhile, dabrafenib and trametinib became available.
Figure 3: The important timelines in the case history of our patient with advanced unresectable salivary duct carcinoma

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  Treatment With Targeted Therapy and Response Top

The patient was started on 150 mg dabrafenib orally twice a day and 2 mg trametinib orally once daily. The patient tolerated the therapy well and had clinical benefit in terms of continuing improvement in the pain and swelling; a restaging scan after 2 months showed stable disease (SD). However, after 5 months of targeted therapy, the patient developed new onset skin nodules over the neck and upper chest wall. Fine needle aspiration and cytology from the cutaneous nodules was suggestive of a high-grade cancer. Additionally, the restaging scan showed progression with new onset enhancing nodularity in the left parotid gland with few ill-defined enhancing areas along the left sternocleidomastoid and occipital muscle regions as well as the left submandibular region.

  Further Therapy at Progression Top

The patient's neuropathy had resolved by this time, and his hematological parameters had normalized. Given his earlier sustained clinical response, he was re-challenged with weekly paclitaxel and carboplatin. Following 6 weeks of chemotherapy, he had further progression in terms of new onset skin nodules and increasing pain and swelling over the parotid region. Considering the limited therapeutic options at this juncture and the ongoing coronavirus disease 2019 (COVID-19) pandemic, he was started on leuprolide and enzalutamide. However, he developed clinical progression in the form of increasing cutaneous lesions (both in size and number), swelling, and pain over the parotid region in 3 months. He was then planned for therapy with gemcitabine with bevacizumab.

  Technical Aspects of the Next-Generation Sequencing Report Top

NGS identifies a large number of genetic variations in the tumor DNA, that provide crucial information for optimal patient care. Treatment guidelines have been developed based on the specific molecular findings. The vast number of variants identified by NGS in the tumor tissue can be attributed to the multistep process of acquiring genetic mutations and tumor heterogeneity. The sensitivity of the tumor is highly context-specific and is influenced by concomitant genomic alterations.

Somatic mutations include SNVs, indels, fusion genes resulting from genomic rearrangements, and copy number variations. These can be activating mutations, such as a missense mutation in the functional or kinase domain of the protein, resulting in a gain of function of the protein, thereby allowing for the loss of regulation of the downstream signaling pathway leading to uncontrolled cell growth and proliferation.

As per the AMP and the College of American Pathologists (CAP) guidelines, the somatic variants are divided into four categories based on their clinical impact: Tier I-variants with strong clinical significance (level A and B evidence); tier II-variants with potential clinical significance (level C or D evidence); tier III-variants with unknown clinical significance; and tier IV-variants that are benign or likely benign.

The Variant Allele frequency (VAF) is vital information that must be reported along with the type of variants. The VAF is an important metric to be taken into account, as it helps the clinicians in the assessment of driver mutations and making decisions regarding the reliability of the variants, the clonal architecture or evolution, and follow up of disease progression.

Annotation is another key metric, and hence, should be included in the reporting format. It can be generic at different gene levels or may be variant-specific, because not all the variants in a single gene have the same effect on the gene function or similar clinical significance. Many patients carry mutations in more than one gene; therefore, annotations about co-mutated genes are important for providing personalized therapies, in which each patient is treated differently according to their genetic profile.

  Excerpts from the Discussion in the Molecular Tumor Board Top

V-raf murine sarcoma viral oncogene homolog B (BRAF), a predominant RAF kinase, is altered in several cancer types. Mutated BRAF is a major oncogenic driver in cancers originating from various tissues. The presence of various forms of mutant BRAF indicates the development of an acquired dependency of the tumor cells on mutant BRAF in these cancers. Being an actionable oncogenic driver, mutant BRAF is reported as a Tier-I mutation; moreover, its presence predicts responsiveness to targeted therapy with BRAF inhibitors. Different cancer types behave differently because of different alterations in their signaling pathways and the cross talks between them. Hence, the presence of BRAF V600E may be associated with an entirely different clinical interpretation in tumors other than melanomas. For instance, in colorectal cancer, the BRAFV600E mutation would direct the clinician towards a combination of targeted therapies (BRAF plus epidermal growth factor receptor [EGFR] inhibitors).

  Natural History of the Disease Top

The natural history of advanced salivary gland cancers (SGC) is highly variable among patients. Some patients remain asymptomatic for long durations without treatment.[1] This has been reported in patients with adenoid cystic carcinomas (ACC) with limited disease in the lung besides acinic cell, and myoepithelial carcinomas.[2] Given the rarity and the variable natural history of the disease, it is difficult to make firm conclusions from single-arm studies with limited sample sizes, as disease stabilization or even a response may be the result of the natural history of the disease rather than that of the therapy. However, our patient was symptomatic and required palliation. Thus, he was started on palliative chemotherapy, and at the same time, an NGS analysis was recommended. Various therapeutic targets and options have emerged in the last decade, and the list continues to expand.[3] [Figure 4] shows a treatment algorithm that can be considered for clinical decision making. [Table 1] summarizes the targeted treatment options available for patients with SGC.
Figure 4: Treatment algorithm incorporating the molecular testing in the treatment of advanced salivary gland tumors

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Table 1: Review of available studies on targeted therapy in salivary gland cancer

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  Androgen Receptor Top

AR expression is commonly seen in salivary duct cancers (SDCs) in >90% of the cases.[3] In patients with metastatic SGC expressing AR, there is some evidence of benefit from androgen deprivation therapy (ADT) with minimal toxicity.[4] In a single-arm, open-label Phase II trial, 36 patients with SGC (majority being SDC) received combined androgen blockade (CAB) with leuprolide (3.75 mg given subcutaneously once in four weeks) and 80 mg bicalutamide orally daily.[5] CAB resulted in an objective response rate (ORR) of 42%, median progression free survival (PFS) of 8.8 months (95% confidence interval CI, 6.3–12.3), and median overall survival (OS) of 30.5 months (95% CI, 16.8-not reached [NR]) at a median follow-up of 15 months.[5]

In another study, 46 patients with AR-expressing SGC were given 160 mg enzalutamide orally once daily.[6] Seven patients (15.2%) had PR as the best response, while 24 patients (52.2%) had SD. The median PFS was 5.5 months (95% CI, 3.7–7.3) at a median follow-up of 11.7 months. At 1 year, the PFS was 24% (95% CI, 14%–42%) and the OS was 66% (95% CI, 52%–83%).

The AR splice variant 7 (AR-V7) is a predictive biomarker for resistance to ADT in prostate cancer. It is reported to be present in approximately 50% of the SDC cases, and might help in refining the selection of patients for ADT.[7] A case report described a patient with SDC who was treated with ADT; at progression, the patient was found to have AR-V7 in the circulating tumor cells.[8] However, another important point to be noted is that the development of AR-V7 in SDC might be independent of prior treatment with ADT. There was an interesting report by Kang et al. in which only one out of three patients treated with ADT derived clinical benefit.[9] The two patients who did not respond to ADT had a high signal for AR-V7 with RNA in-situ hybridization. The responding patient was AR-V7-negative by the same technique.

  Human Epidermal Growth Factor Receptor 2 Alterations Top

Approximately 40% of SDC and 30% of mucoepidermoid carcinomas overexpress HER2.[9] Conversely, HER2 is rarely expressed in ACC (around 4%).[10] The role of trastuzumab has been explored in multiple small studies. In a retrospective study, the combination of paclitaxel, carboplatin, and trastuzumab (TCH) was given to 13 patients (8 in the adjuvant setting and 5 in the palliative setting) with SDC whose tumors were positive for HER2/neu (1–3+ by IHC) once in 3 weeks for 6 cycles followed by trastuzumab for varying time periods.[11] The ORR was 100% (n = 5), while the median duration of response (DOR) was 18 months (range, 8–52 months). A complete remission was noted in 1 patient, which was sustained for 52 months after the start of TCH.[11] In another single-arm Phase II study from Japan, 57 patients with HER2-positive SDC received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks along with docetaxel 70 mg/m2 every 3 weeks.[12] The ORR was 70.2%, and the median PFS and OS were 8.9 months (95% CI, 7.8–9.9 months) and 39.7 months (95% CI, NR), respectively. Grade 3/4 febrile neutropenia occurred in 74% of the patients, but no significant cardiac toxicity was reported.

It should be noted that single-agent trastuzumab has low activity in HER2/neu-positive SGC. Single agent encouraging activity has been reported for trastuzumab emtansine (T-DM1). In the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) study, two out of the three patients with SGC had sustained PR with T-DM1 (PR lasting for 9 months in the patient with mucoepidermoid carcinoma and 2 years in the patient with squamous cell cancer).[13] In yet another study presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO), 9 of 10 patients with SGC achieved PR with T-DM1 (ORR, 90%).[14]

In the MyPathway study, a multiple basket, nonrandomized, multi-center study, 15 patients with SGC with HER2 amplification/overexpression (with or without mutations) were given trastuzumab + pertuzumab. The ORR was 60% (1 CR and 8 PR) with a median DOR of 9.2 months. The median PFS and OS were 8.6 (95% CI, 2.3 - NR) and 20.4 months (95% CI, 8.2 - NR), respectively.[15]

  Epidermal Growth Factor Receptor Pathway and Harvey Rat Sarcoma Viral Oncogene Analog (Hras) Top

Of 70 patients with SCC, missense mutations in the EGFR pathway were identified in 13 (18.6%). Ten patients were noted to have RAS mutation (14.3%), while 5 (7.1%) had mutations in the PIK3CA gene and 1 (1.4%) in the EGFR gene.[16] However, no EGFR deletions were identified by direct sequencing. The presence of mutations in the EGFR pathway was associated with a shorter disease-free survival (DFS) (P = 0.011) and OS (P = 0.049); similarly, the presence of HRAS mutations was associated with a shorter DFS (P = 0.01) and OS (P = 0.024). HRAS mutations were observed in 13 out of 117 (11.1%) patients in a study evaluating the genomic landscape in SGC.[17]

In a study presented at ASCO 2020, 13 patients with advanced SGC who had received prior systemic therapy (one to three prior regimens, progressed within the preceding 6 months) and had mutated HRAS received the farnesyl transferase inhibitor, tipifarnib.[18] One patient attained a PR, and seven had SD (61.5% clinical benefit rate) with a median DOR of 9 months. The median PFS and OS were 7 (95% CI, 5.9–10.1) and 18 months (95% CI, 9.6–22.4), respectively, with 58.6% of the patients being alive at 1 year. The most commonly identified HRAS mutation was Q61R (54% of the patients); however, the gene variant, co-occurring PIK3CA alterations, and allele frequency had no correlation with the outcomes, contrary to the study in head and neck squamous cell carcinomas. In another study, it was noted that PIK3CA mutations tend to co-occur almost always with HRAS mutations.[17]

  Vascular Endothelial Growth Factor, Fibroblast Growth Factor Receptor, and Ckit Top

Various studies have incorporated the vascular endothelial growth factor (VEGF) inhibitors in the treatment of SGC. In a Phase-II, single-arm study, patients with ACC (n = 33) post progression on systemic chemotherapy/immunotherapy/radiotherapy were given lenvatinib 24 mg orally daily.[19] Prior targeted therapy had been administered to 27% of the patients (18% had received other VEGF TKIs as well). At a median follow up of 5.2 months, 16% had PR, and 75% had SD with a median PFS of 17.5 months (95% CI, 7.2-NR).[19] The usual adverse effects of lenvatinib were reported, with grade 3/4 hypertension being the most common (28%); 70% of the patients required dose reductions.

The ORRs to sorafenib and axitinib in patients with recurrent metastatic SGC have been reported to be 16% and 9%, respectively.[20],[21] In a subgroup analysis with incorporation of NGS data, it was hypothesized that patients with ACC with 4q12 amplification might derive particular benefit from axitinib.[21] In another recent study presented at the ASCO 2020 meeting, 60 patients were randomly allocated equally to axitinib and observation.[22] The 6-month PFS rates were 73% (95% CI, 54.8–88.1%) and 23% (95% CI, 9.3–41.1%), respectively (hazard ratio, 0.19; 95% CI, 0.08–0.45; P < 0.001).[22] The median PFS were 10.8 and 2.8 months, respectively, at a median follow up of 25 months. There was no PR reported with either sunitinib or nintedanib, and approximately 57% and 75% of the treated patients had SD lasting more than 6 months with sunitinib and nintedanib, respectively.[23],[24]

There are reports of the inclusion of bevacizumab in the treatment of advanced SGC in an attempt to increase the responses. A case report described a patient with SDC (HER2 3+ by IHC) treated with the combination of trastuzumab, lapatinib, and bevacizumab. The patient had a sustained response on this therapy for more than 24 months despite the use of trastuzumab for 20 months in the previous line of therapy as well.[25] This forms the basis for the consideration of the use of bevacizumab in patients with advanced SGC who have progressed on standard lines of therapy, as was the case with our patient, in whom bevacizumab was combined with gemcitabine in an attempt to improve the response.

Overexpression of the fibroblast growth factor receptor 1 (FGFR1) is commonly observed in ACC. Dovitinib, a drug that suppresses the activity of FGFR has been studied in a Phase II trial.[26] Out of a total of 34 evaluable patients, two (6%) had a PR, while 22 (65%) had SD for more than 4 months.[26] The median PFS and OS were 8.2 (95% CI, 7.3–11.0) and 20.6 months (95% CI, 7.6 - NR), respectively. Targeting c-KIT with imatinib and dasatinib has been tried, but has failed to demonstrate any clinically meaningful activity, most likely due to the lack of c-KIT being a driver of the pathway.[27]

  Pi3k/akt/mtor Pathway Top

There are some data that suggest that high expression of genes in the AKT/mTOR pathway is associated with less aggressive disease and even an improved survival.[28] Everolimus was evaluated in a Phase II study (n = 34) for ACC, and it led to SD for more than 6 months in 38% of the patients.[29]

  Histone Deacetylase Inhibitors Top

Vorinostat, an histone deacetylase inhibitor, has been tried in a Phase II study (n = 30) with 7% of the patients achieving PR and 75% having SD lasting more than 6 months.[30]

  Neurotrophic Tropomyosin Receptor Kinase Top

The Mammary analog secretory carcinoma (MASC) of the salivary gland shares both histologic and genetic similarities with carcinomas of the breast. Neurotrophic tropomyosin receptor kinase 3 gene activating fusions have been reported in nearly all cases of MASC SGC, the most common one being ETV6-NTRK3 as a result of balanced translocation t(12;15).[31]

Larotrectinib and entrectinib are selective oral NTRK inhibitors. On a pooled analysis of three Phase 1/2 clinical trials with larotrectinib for MASC of salivary glands (n = 21), an ORR of 90% with a median DOR of 35 months was observed.[32] In another pooled analysis of MASC SGC treated with entrectinib (n = 7), the ORR was 86% with a DOR ranging between 3 and 17 months.[33] Both larotrectinib and entrectinib have been approved by the Food and Drug Administration (FDA) for use in patients with tumors harboring NTRK gene fusions (tissue-agnostic approval). Larotrectinib has a better toxicity profile than entrectinib; the latter led to high rates of transaminitis (all grades, 73%), congestive heart failure (3.4%), and skeletal fractures (5% in adults and 23% in pediatric patients).[34]

  Braf Mutation Top

BRAF mutations are extremely rare in SGCs. No BRAF mutations were reported by Kato et al. in their genomic analysis of 117 patients with SGCs.[17] In the MyPathway study mentioned above, a patient with BRAFV600E mutated SGC was treated with vemurafenib and had a PFS of 18.5 months.[15] In a case report, a male patient with widely metastatic SDC harboring a BRAFV600E mutation was treated with first-line dabrafenib and trametinib.[35] He experienced a PR which was sustained for nearly 13 months, but later showed disease progression in the bones. In a Phase II study of vemurafenib for nonmelanoma cancers with a BRAFV600 mutation, one patient with SDC attained a PR.[36]

In our patient, the response to dabrafenib plus trametinib lasted for only 4 months, which appears to be lower than what would be expected with the use of targeted therapy directed at a molecular driver mutation; earlier case reports appear to have had more durable responses. However, it should be noted that previous studies on BRAF inhibitors for SGC are scarce, and there might be a publication bias due to the lack of reporting the patients who had poor response, as was observed in our case.

The pathways that have been implicated in the intrinsic resistance to BRAF inhibitors involve RAC1 mutations and PTEN loss.[37] Acquired resistance can be classified as MAP/ERK pathway dependent or independent. Activating mutations of NRAS constitute the most common MAP/ERK dependent resistant mechanism, while upregulation of the PI3K/AKT signaling pathway is an important mechanism for MAP/ERK independent resistance.[38] Other pathways that may play a role include changes in the tumor microenvironment. Since the patient discussed in the present report initially responded clinically and then later progressed, one of the acquired resistance pathways could have contributed to this. This could have been ascertained if NGS testing of a re-biopsy specimen had been performed.

  Immunotherapy Top

No discussion for systemic therapy is complete without considering the role of immunotherapy. The Phase I KEYNOTE-028 study enrolled 26 patients with recurrent metastatic SGC in whom the programmed cell death ligand 1 (PD-L1) was detected by 22C3 antibody (membranous staining ≥1% tumor cells).[39] Pembrolizumab led to ORR of 12% with a median DOR, PFS and OS of 4 (range, 4–21), 4 (95% CI, 2–5) and 13 months (95% CI, 6-NR), respectively at a median follow up of 20 months.[39] In a subsequent Phase II study for advanced MSI-H/mismatch repair-deficient (dMMR) noncolorectal cancer, pembrolizumab led to a clinical benefit in SGC patients, however, it should be noted that only 2 of the 233 patients enrolled in the study had SGC.[40] In another Phase II study which combined pembrolizumab and vorinostat in patients with advanced SGC, there were 4 (16%) PR (including 1 lymphoepithelioma-like carcinoma, 2 acinic cell, 1 ACC), and 14 SD (56%). The median PFS and OS were 6.9 (95% CI, 4.1 - NR) and 14 months (95% CI, 8.5-NR) at median follow up of 13 months.[41] In the MyPathway study, a patient of SGC treated with high TMB treated with atezolizumab, had PFS of 5.7+ months.[15] In a real-world data of six patients of rare head and neck cancers treated with nivolumab in the second line and beyond setting, there were 2 patients with SGC, out which 1 patient of ACC had a PFS of 2 months while another patient with mucoepidermoid cancer had a PFS of 12 months.[42]

  Other Rare Mutations Top

In the MyPathway study, a patient with SGC harboring a patched homolog-1 (PTCH-1) mutation treated with vismodegib had a PFS of 14.3 months.[15] There was a report of 2 patients with SGC (adenocarcinoma and ACC) who had progressive lung metastasis and were treated with tamoxifen and toremifen, respectively; both had a very prolonged PFS (10 and 3 years, respectively).[43] It is interesting that both the patients were estrogen receptor (ER)-negative on IHC. The authors commented that tamoxifen has multiple actions that are ER-independent, including programmed cell death and growth inhibition and inhibition of multidrug resistance (MDR) proteins and protein kinase C, besides reducing the serum VEGF levels.[44] There was an older case report of a patient with recurrent inoperable ACC treated with tamoxifen who attained a PR after 18 months of therapy; the response was maintained for years when the patient died due to a noncancer-related cause.[45] In a Phase II trial, 25 patients with advanced ACC were treated with bortezomib; the rationale for this was the expression of the nuclear factor kappa B (NF-κB) in ACC which can be inhibited by bortezomib. Though there was no objective response, SD was achieved in 71% of the patients with a median PFS and OS of 6.4 (95% CI, 1.6–8.7) and 21 months (95% CI, 15.8–38), respectively.[46]

  Salivary Duct Carcinoma Top

SDC constitutes an aggressive subtype of SGC, and the patients usually present with locoregional and/or distant metastasis. The platinum-taxane combination leads to responses in approximately 40% of the patients, but these are rarely long-lasting.[47] The most important targets in SDC include HER2 amplification (about 40%), PI3K/AKT/mTOR pathway mutations (about 50%), RAS (about 25%) and NOTCH1 (15%) mutations, and AR overexpression (90%).[48]

  Conclusions Top

SGC are rare tumors associated with a poor prognosis and limited options of systemic chemotherapy. With the rising use of NGS, it is expected that more actionable targets will be detected, and this will expand the physician's armamentarium for improving the outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts to conceal identity will be made, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Su YX, Roberts DB, Hanna EY, El-Naggar A, Saylam G, Frank SJ, et al. Risk Factors and Prognosis for Myoepithelial Carcinoma of the Major Salivary Glands. Ann Surg Oncol 2015;22:3701-7.  Back to cited text no. 2
Schmitt NC, Kang H, Sharma A. Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy. Oral Oncol 2017;74:40-8.  Back to cited text no. 3
Williams L, Thompson LD, Seethala RR, Weinreb I, Assaad AM, Tuluc M, et al. Salivary duct carcinoma: The predominance of apocrine morphology, prevalence of histologic variants, and androgen receptor expression. Am J Surg Pathol 2015;39:705-13.  Back to cited text no. 4
Fushimi C, Tada Y, Takahashi H, Nagao T, Ojiri H, Masubuchi T, et al. A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma. Ann Oncol 2018;29:979-84.  Back to cited text no. 5
Ho AL, Foster NR, Zoroufy AJ, Worden FP, Price KAR, Adkins D, et al. Alliance A091404: A phase II study of enzalutamide (NSC# 766085) for patients with androgen receptor-positive salivary cancers. J Clin Oncol 2019;37(15)suppl:6020.  Back to cited text no. 6
Cappelletti V, Miodini P, Reduzzi C, Alfieri S, Daidone MG, Licitra L, et al. Tailoring treatment of salivary duct carcinoma by liquid biopsy: ARv7 expression in circulating tumor cells. Ann Oncol 2018;29:1598-600.  Back to cited text no. 7
Kang H, Antonarakis ES, Luo J, Zheng Q, Rooper L, De Marzo AM, et al. Detection of AR-V7 transcript with RNA in situ hybridization in human salivary duct cancer. Oral Oncol 2018;84:134-6.  Back to cited text no. 8
Corrêa TS, Matos GD, Segura M, Dos Anjos CH. Second-line treatment of HER2-positive salivary gland tumor: Ado-trastuzumab emtansine (T-DM1) after progression on trastuzumab. Case Rep Oncol 2018;11:252-7.  Back to cited text no. 9
Glisson B, Colevas AD, Haddad R, Krane J, El-Naggar A, Kies M, et al. HER2 expression in salivary gland carcinomas: Dependence on histological subtype. Clin Cancer Res 2004;10:944-6.  Back to cited text no. 10
Limaye SA, Posner MR, Krane JF, Fonfria M, Lorch JH, Dillon DA, et al. Trastuzumab for the treatment of salivary duct carcinoma. Oncologist 2013;18:294-300.  Back to cited text no. 11
Takahashi H, Tada Y, Saotome T, Akazawa K, Ojiri H, Fushimi C, et al. Phase II trial of trastuzumab and docetaxel in patients with human epidermal growth factor receptor 2-positive salivary duct carcinoma. J Clin Oncol 2019;37:125-34.  Back to cited text no. 12
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