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Received: 1 September 2022 Revised: 9 December 2022 Accepted: 16 January 2023
DOI: 10.1002/hed.27307

CLINICAL REVIEW

A molecular guide to systemic therapy in salivary gland

carcinoma

Alice N. Weaver MD, PhD 1 | Stephanie Lakritz MD 1 | Divneet Mandair MD 2 |

Mark B. Ulanja MD, MPH 3 | Daniel W. Bowles MD 1,4

1
Division of Medical Oncology, University
of Colorado School of Medicine, Denver, Abstract
Colorado, USA Salivary gland carcinomas (SGC) are a rare and variable group of head and
2
Division of Hematology/Oncology, neck cancers with historically poor response to cytotoxic chemotherapy and
University of San Francisco California,
immunotherapy in the recurrent, advanced, and metastatic settings. In the
San Francisco, California, USA
3
Christus Ochsner St. Patrick Hospital,
last decade, a number of targetable molecular alterations have been identi-
Lake Charles, Louisiana, USA fied in SGCs including HER2 upregulation, androgen receptor overexpres-
4
Rocky Mountain Regional Veterans sion, Notch receptor activation, NTRK gene fusions, and RET alterations
Affairs Medical Center, Aurora,
which have dramatically improved treatment outcomes in this disease.
Colorado, USA
Here, we review the landscape of precision therapy in SGC including cur-
Correspondence rent options for systemic management, ongoing clinical trials, and promis-
Daniel W. Bowles, Medical Oncology,
ing future directions.
University of Colorado, 12801 E 17th Ave,
MS 8117, Aurora, CO 80045.
Email: daniel.bowles@cuanschutz.edu KEYWORDS
adenoid cystic carcinoma, mucoepidermoid carcinoma, precision therapy, salivary duct
carcinoma, salivary gland cancer

1 | INTRODUCTION inhibition when given as monotherapy.6,7 This

Salivary gland carcinomas (SGC) are a heterogenous col-
lection of tumors originating from the major salivary
glands (parotid, submandibular, and sublingual) as well
as hundreds of minor salivary glands dispersed through-
out the aerodigestive tract.1,2 SGCs can be classified into
more than 20 subtypes, including mucoepidermoid carci-
noma (MEC), adenoid cystic carcinoma (ACC), salivary
duct carcinoma (SDC), acinic cell carcinoma (AciCC),
and secretory carcinoma (SC) with widely variable clini-
cal behavior. While each histiotype is individually rare,
the group represents approximately 5% of head and neck
cancers.3–5 Surgery and radiation are the mainstays of
local SGC therapy, but treatment options for inoperable,
recurrent, and metastatic disease have been limited by
poor response to cytotoxic chemotherapy.5 Similarly,
SGCs have not responded well to immune checkpoint
historically challenging treatment paradigm has been
dramatically altered in the last decade with the identifica-
tion of multiple targetable molecular alterations in SGCs
including gene fusions, mutations, and activation of key
signaling pathways.8,9 Here, we review the current state
of SGC clinical management and highlight future direc-
tions for the use of targeted therapies.
2 | C L I NI C A L P R E SE NT A T I O N
AND EVALUATION
Salivary gland cancers typically present as a palpable
mass which can be associated with pain, facial nerve
palsy, lymphadenopathy, trismus, ulceration, and fistu-
las.10 Ultrasound (US) is the preferred initial evaluation
for tumors in the major salivary glands, especially the

© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Head & Neck. 2023;1–12. wileyonlinelibrary.com/journal/hed 1


2 WEAVER ET AL.
superficial lobe of the parotid gland.11 When aggressive
features are present, or the mass is in the deep parotid
lobe, minor glands, or sublingual glands, a contrasted
MRI or CT should be performed for further evaluation.12
PET-CT is rarely part of the initial evaluation, as both
malignant and benign tumors exhibit glucose uptake, but
this modality may play a role in staging and surveillance
when locoregional spread or distant metastases are pre-
sent. Lymphovascular invasion, extranodal extension,
facial nerve involvement, cervical lymph node spread,
and skull base infiltration can occur and predict poor
prognosis.13–17 Lymph node involvement at time of diag-
nosis is variable but more commonly seen in MEC and
SDC while distant metastasis, especially to the lungs, is
more likely to be seen in ACC.13 US-guided fine needle
aspiration (FNA) is the favored biopsy method, although
specificity is widely variable ranging from 63% in MEC to
85% in adenocarcinoma.18–20 Expert pathology review is
essential to an accurate diagnosis given the overlapping
features between different subtypes and frequent need for
ancillary testing.
3 | TREATMENT O PTIONS FOR
LOCAL DISEASE
Surgery with or without adjuvant radiation is the cor-
nerstone of treatment for localized SGC regardless of
subtype. Surgical techniques vary with options includ-
ing glandular excision and wide local excision with the
goal of obtaining tumor free margins.8,13 Ipsilateral
neck dissection is indicated if lymph node metastases
are present at time of diagnosis.12,21 Adjuvant radio-
therapy (RT) is recommended for most ACC based on
improved overall survival (OS) in early-stage disease
and increased local control in later stages.22–24 In
non-ACC SGC, the benefit of post-operative RT is lim-
ited to tumors with high-risk features including
pT3-T4, close or positive margins, vascular or peri-
neural invasion, multiple lymph node metastases, and
extracapsular extension.25–31 Adjuvant chemoradiation
has shown mixed benefit in retrospective studies, but
the first randomized data for this approach is pending
the results of NCT01220583, NCT02776163, and
NCT02998385.26,32–34 Definitive RT can be considered
for inoperable disease, but long-term control rates are
<50% and 20% for ACC and non-ACC cancers, respec-
tively.26 Definitive chemoradiation with platinum-
based therapy is currently limited to palliative or
investigational use.35 Local treatment is highly effec-
tive in achieving locoregional control, as evidenced by
a single center retrospective study demonstrating
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recurrence at the primary disease site in only 7.2% of
patients after 5 years.36 However, 43% of patients devel-
oped distant metastasis ultimately requiring some form
of systemic therapy.
4 | MANAGEMENT OF
IN O PE R A B L E , RE C U R R E N T , O R
METASTATIC DISEASE: FOCUS ON
P R E C I S I O N TH ER A P Y
4.1 | Mucoepidermoid carcinoma
Mucoepidermoid carcinoma (MEC) is the most common
SGC subtype and most often occurs in the parotid gland.
MECs have a characteristic imaging appearance with a
well-circumscribed (low grade) or infiltrative (high grade)
mass associated with spread along the facial nerve into
the mastoid segment of the temporal bone.10 The tumors
consist of epidermoid cells, mucin-secreting cells, and
intermediate cells, and histologic grade is predictive of
prognosis.37 Five-year OS ranges from 98% for low grade/
localized tumors to 25% for high grade/metastatic MEC,
and disease recurrence is a mixture of primary relapse,
regional lymph node spread, and distant metastasis, most
commonly to the lungs.38–40 High grade or metastatic
MEC has typically been treated with single-agent or com-
bination chemotherapy with cisplatin, fluorouracil
and/or paclitaxel, although clinically significant
responses are infrequent and short-lived (Table 1).6,7,41–59
A phase Ib trial of pembrolizumab in PD-L1-positive
SGC, including 10 patients with adenocarcinoma and
three patients with MEC, reported a disappointing objec-
tive response rate (ORR) of 12% with median duration of
response only 4 months.6
Over 50% of MECs contain a unique t(11;19)(q21-22;
p13) translocation leading to a CRTC1-MAML2 fusion gene
which constitutively activates CREB-mediated transcrip-
tion.60 While t(11;19)(q21-22;p13) detection has a diagnostic
role for MEC, there is conflicting data on whether the trans-
location is predictive of survival.37,61,62 CRTC1-MAML2
fusion-positive cells have demonstrated in vivo sensitivity to
EGFR-targeted therapy in MEC xenograft models, however
there are not yet clinical trials in this context.63 There are
only isolated case reports of response to EGFR inhibition in
the general MEC population.64 Human epidermal growth
factor receptor 2 (HER2) amplification is also found in up
to one-third of MEC cases, and there is great interest in tar-
geted therapies for HER2-positive disease as described in a
later section. Other common genetic findings include
CDKN2A, TP53, CDKN2B, BAP1, PIK3CA, HRAS, BRCA,
and ERBB2 alterations.65
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WEAVER ET AL. 3

TABLE 1 Treatment outcomes in recurrent/metastatic salivary gland carcinoma

Median duration of
Tumor type Treatment Objective response rate % (n) response (mos)
Any Chemotherapy 15–35 Widely variable
Pembrolizumab6 12 (3) 3.9
7
Nivolumab 3.8 (2) to 8.7 (4) 1.8–4.9
42,43
ACC Lenvatinib 11.5 (3) to 15.6 (5) 9.1–17.5
44,45
Axitinib 7.7 (2) to 9.1 (3) 5.5–5.7
Apatinib46,47 13.9 (10) to 33.8 (22) 12–17.7
48
AL101 11.6 (9) Pending
49
HER2+ TCH 100 (5) 18
Docetaxel + Trastuzumab 50
70.2 (40) 8.9
Pertuzumab + Trastuzumab51 60 (9) 9.2
52
T-DM1 90 (9) Not reached
53
AR+ Bicalutamide ± Goserelin 18 (6) 11
Bicalutamide + Triptorelin 54
64.7 (11) 11
Bicalutamide + Leuprorelin acetate55 41.7 (15) 8.8
56
Enzalutamide 4.3 (2) 5.6
57
Abiraterone 21 (5) 5.8
58
NTRK-fusion positive Larotrectinib 90.9 (10) 35.2
Entrectinib59 85.7 (6) 10

Note: Objective response rates are reported as percentages with absolute numbers in parentheses; absolute numbers are not provided for chemotherapy
response as this is a composite of numerous studies.
Abbreviations: ACC, adenoid cystic carcinoma; AR, androgen receptor; HER2, human epidermal growth factor receptor; NTRK, neurotrophic tyrosine receptor
kinase; RT, radiation; TCH, docetaxel + carboplatin + trastuzumab; T-DM1, ado-trastuzumab emtansine.

4.2 | Adenoid cystic carcinoma
Adenoid cystic carcinoma (ACC) is the second most fre-
quent subtype of malignant SGCs, representing about
10% of diagnoses.66 ACC is often found in the minor sali-
vary glands with high rates of local infiltration and, occa-
sionally, discontinuous perineural skip lesions.10
Prognosis for ACC is poor with 24%–45% survival at
5 years.14 Response rates to systemic chemotherapy are
low across a variety of regimens including cisplatin
monotherapy, cisplatin plus anthracycline, cisplatin plus
gemcitabine, CAP (cyclophosphamide, doxorubicin, and
cisplatin), paclitaxel, mitoxantrone, vinorelbine, and
epirubicin.67–71 CAP is the most commonly employed
therapy; a systematic review in patients with ACC
showed an ORR of 25% with variable duration ranging
from 6 to 77 months.72 A more recent trial of CAP found
an ORR of 14.3% and disease control rate of 85.7% with a
median OS 23.4 months.73 Vinorelbine plus cisplatin had
an increased ORR of 35% with disease control rate of
87.5%, but median OS was shorter at 16.9 months.74
These regimens come with substantial toxicity which has
limited their use. Non-selected immunotherapy with
checkpoint inhibition has similar benefit; for example,
data from the phase II NISCAHN trial of nivolumab in
46 patients with ACC showed a 6-month non-progression
rate of 33%, as compared with 14% in non-ACC patients.7
However, median progression free survival (PFS) was just
4.9 months. None of these regimens are preferred over
the others for efficacy, so choice is primarily guided by
side effect profile.
Multikinase inhibitors (MKIs) focused on vascular
endothelial growth factor (VEGF) are another option for
systemic therapy in ACC, albeit with only modest bene-
fit (Table 1). Two studies evaluating lenvatinib, an MKI
approved for the treatment of renal cell, hepatocellular,
and endometrial cancers, showed partial responses in
11.5% and 15.6% of patients with recurrent/metastatic
ACC with median PFS of 9.1 and 17.5 months.42,43
Another two trials assessed axitinib, an MKI approved
to treat renal cell carcinoma, and found partial response
in 8%–9% and stable disease in 50%–75% of ACC
patients.44,45 The selective VEGF2 inhibitor, rivoceranib
(also called apatinib), has also been studied in advanced
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4 WEAVER ET AL.

TABLE 2 Active clinical trials in salivary gland carcinoma

Trial identifier Phase Investigational therapies Molecular markers Status

Anti-androgen
NCT01969578 II Bicalutamide + Triptorelin AR+ Recruiting
NCT03942653 II Goserelin + Pembrolizumab AR+ Recruiting
HER2-targeted
NCT03602079 I/II A166 HER2+ Not recruiting
NCT03740256 I HER2-targeted CAR-T HER2+ Recruiting
NCT04639219 II Trastuzumab deruxtecan HER2+ Not recruiting
NCT04620187 II Adjuvant T-DM1 HER2+ Recruiting
NCT05408845 II T-DM1 HER2+ Not yet recruiting
NCT04704661 I Ceralasertib + Trastuzumab deruxtecan HER2+ Recruiting
NTRK inhibition
NCT02568267 II Entrectinib NTRK/ROS, ALK Recruiting
NCT025764131 II Larotrectinib NTRK Recruiting
Other molecular therapy
NCT02069730 Selinexor, EGFRi, HER2i, FGFRi, C-KITi, anti-AR, Matched Recruiting
NOTCHi, MEKi, or PI3Ki
NCT03781986 I/II APG115 ± Carboplatin p53 Recruiting
NCT05010629 II 9-ING-41 + Carboplatin Recruiting
NCT04209660 II Lenvatinib + Pembrolizumab Recruiting
NCT04291300 II Lutetium-177-PSMA PSMA Recruiting
NCT05074940 II Amivantamab Not yet recruiting
NCT04910854 II Surufatinib Recruiting
Immunotherapy
NCT03749460 I/II Ipilimumab + Nivolumab + RT Recruiting
NCT03360890 II Pembrolizumab + Docetaxel Recruiting
NCT04895735 II Pembrolizumab + Pemetrexed Not yet recruiting
NCT02628067 II Pembrolizumab Recruiting
NCT04825938 II Neoadjuvant torpalimab Not yet recruiting
NCT04249947 I P-PSMA-101 CAR-T PSMA Recruiting
NCT05000892 II Sintilimab + chemotherapy Recruiting

Abbreviations: AR, Androgen receptor; ALK, anaplastic lymphoma kinase; CAR-T, chimeric antigen receptor T-cell; EGFR, epidermal growth factor receptor;
FGFR, fibroblast growth factor receptor; HER2, human epidermal growth factor receptor; i, inhibition; NTRK, neurotrophic tyrosine receptor kinase; PI3K,
phosphoinositide 3-kinase; PSMA, prostate specific membrane antigen; RT, radiation therapy; T-DM1, ado-trastuzumab emtansine.

ACC with an ORR of 13.9%–33.8%.46,47 These were all
partial responses, and the vast majority occurred in
patients without prior MKI therapy. It is unclear
whether the results of VEGF inhibition are target spe-
cific or universal to antiangiogenic tyrosine kinase
inhibitors. Both lenvatinib and axitinib are included as
options in the National Comprehensive Cancer Network
(NCCN) guidelines for relapsed/metastatic disease.62
ACC are occasionally found to have mutations in epi-
dermal growth factor receptor (EGFR), however EGFR
inhibition has not proven beneficial as monotherapy in
multiple phase II trials75–78,6. Combination with
platinum-based chemotherapy was more promising with
an OR >40%.79
The most common molecular alteration and the main
driver of progression in ACC is overexpression of the
nuclear transcription factor MYB, occurring in 60%–80%
of tumors.9,66 This is usually associated with the t(6;9)
(q23;p23) translocation leading to a MYB-NFIB fusion
oncoprotein. Preclinical studies using direct MYB inhibi-
tors such as all-trans retinoic acid (ATRA) confirmed
in vitro binding and decreased ACC tumor growth.80
However, a phase II trial of ATRA in recurrent/
metastatic ACC showed no responses in 18 enrolled

WEAVER ET AL.
patients with 61% achieving stable disease for a median
duration of 3.7 months.81 Alternative mechanisms to tar-
get MYB are under evaluation including the phase I
MYPHISMO trial (NCT03287427) using a TetMYB vac-
cine plus anti-PD-1 therapy, as well as a phase II trial of
amivantamab which is a bispecific inhibitor of the MYB
transcription target MET and EGFR (Table 2). It is possi-
ble that therapies targeting other MYB transcription tar-
gets such as MYC, BCL2, and IGF2 may be beneficial in
MYB-overexpressing ACC, but in vitro data have thus far
been mixed.8,82
Notch signaling abnormalities may also play an
important role in the advanced or recurrent disease set-
ting, as nearly a quarter of ACC patients have activat-
ing Notch receptor mutations.78 A phase II clinical
trial assessing the clinical role of AL101, a selective
gamma-secretase inhibitor, in patients with advanced
ACC and activating Notch mutations was recently
completed (NCT03691207). Early results were encour-
aging with an overall disease control rate of 69% in
77 patients treated at two dose levels including nine
patients with partial response (11.6%) and 44 with sta-
ble disease (57.1%).48 Unfortunately, clinical use of this
drug was hampered by high incidence of diarrhea (73%
of all patients with 11% grade 3) and fatigue (49% of
all patients and 5% grade 3). Therapies targeting other
steps in the Notch signaling pathway have not yet
proven effective.83
A new target of interest in ACC is prostate-specific
membrane antigen (PSMA), a transmembrane glycopro-
tein first studied as an imaging and therapeutic target in
prostate cancer. Salivary gland toxicity is among the
most prominent adverse effects of PSMA-targeted radio-
therapy, occurring in up to 30% of patients and often
leading to treatment discontinuation.84 This finding
prompted further investigation of PSMA in salivary
gland malignancies which demonstrated positive immu-
nohistochemical expression in 97% of benign tumors,
77% of malignant tumors, and 59% of normal salivary
glands adjacent to tumor.85 A corresponding imaging
study showed clinically relevant PSMA ligand uptake on
68
Ga-PSMA PET-CT in 93% of ACC patients and 40% of
SDC patients in the locally advanced, recurrent, and
metastatic setting.86 Data regarding therapeutic benefit
are limited to a small retrospective review of six patients
with SGC, including four with ACC, receiving palliative
177
Lu-PSMA which resulted in rapid relief of tumor-
related symptoms in four patients and radiologic
response in two with one partial response and one stable
disease.87 Clinical trials are ongoing to evaluate both
177
Lu-PSMA radioligand therapy and PSMA-targeted
chimeric antigen receptor T-cells (CAR-T) in SGC
(Table 2).
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5
4.3 | Salivary duct carcinoma and
adenocarcinomas
Salivary duct carcinoma (SDC) is typically found in the
major salivary glands, especially the parotid gland, and
comprises around 5% of all salivary gland malignancies.21
Diagnosis is made histologically based on hematoxylin
and eosin stain findings which resemble ductal carci-
noma of the breast.37 These tumors are extremely aggres-
sive: 49%–72% of patients already have regional lymph
node involvement at time of diagnosis and 4%–10% have
distant metastases which most commonly involve the
lungs, bones, and lymph nodes.88,89 Median overall sur-
vival ranges from 48 to 79 months for localized disease to
as short as 6 months in the case of widespread metasta-
sis.90 There is little guidance for the use of chemotherapy
in SDC as the rarity of the disease limits prospective tri-
als. Platinum-based regimens are the most reported in
case series including carboplatin plus paclitaxel with an
ORR of 39%, carboplatin plus docetaxel with an ORR of
50%, cisplatin plus gemcitabine, and CAP.91 Checkpoint
inhibitors are rarely used but could be considered for
SDC with tumor mutation burden > = 10 mut/MB.
With histologic similarity to invasive ductal carci-
noma, it is notable that HER2 is an important biomarker
for SDC with upregulation found in 36%–51% of
tumors.18,92,93 The superior efficacy of HER2-targeted
therapy in this population has now been demonstrated in
numerous clinical studies (Table 1). Retrospective analy-
sis of a small group of patients with metastatic HER2+
SDC treated with paclitaxel, carboplatin, and trastuzu-
mab for six cycles followed by maintenance trastuzumab
found objective response in all five patients with median
duration of 18 months.49 A phase II single arm trial
involving 57 HER2-positive advanced or recurrent SDC
patients treated with docetaxel and trastuzumab found
an ORR of 70.2% with a clinical benefit rate of 84.2% and
median OS 39.7 months.50 MyPathway, a multiple basket,
open-label, non-randomized study including 15 patients
with advanced SDC with HER2 amplification and/or
overexpression treated with combination pertuzumab
and trastuzumab demonstrated an ORR of 60%.51
Another basket trial evaluating the antibody-drug conju-
gate ado-trastuzumab emtansine or T-DM1 found an
ORR of 90% in HER2-positive salivary gland tumors.52
Finally, SDC accounted for some of the most pronounced
tumor responses in the phase I trial of trastuzumab der-
uxtecan (T-DXd) in HER2-positive non-breast/non-
gastric solid tumors which included eight patients with
SGC.94 Thus, HER2 status should be assessed in all SDC
and potentially other SGCs such as MEC for consider-
ation of first line HER2-directed treatment. Further eval-
uation of T-DM1, T-DXd, and HER2-targeted chimeric

6 WEAVER ET AL.
antigen receptor T-cells in advanced SGCs is underway
(Table 2).
The most common molecular characteristic in SDC,
however, is androgen receptor (AR) expression which
occurs in 80% of patients.18,53,95 A phase II trial of recur-
rent/metastatic or unresectable locally advanced SDC
and adenocarcinoma not otherwise specified (NOS) trea-
ted with combined AR blockade of leuprorelin acetate
and bicalutamide showed an ORR of 41.7% and clinical
benefit rate of 75%, with median PFS 8.8 months and
median OS 30.5 months.55 These findings are supported
by a retrospective study in the adjuvant setting compar-
ing bicalutamide, luteinizing hormone-releasing hor-
mone (LHRH) analog, or combination therapy following
complete tumor resection. Three-year disease-free sur-
vival increased by 20% in the treatment groups as com-
pared with control.96 In contrast, anti-androgen therapy
with enzalutamide alone failed to meet the primary end-
point of confirmed response in the phase II Alliance
A091404 trial.56 Given the low toxicity profile, androgen
deprivation therapy (ADT) is an attractive first- or
second-line treatment option for SDC and adenocarci-
noma NOS with combined blockade favored over mono-
therapy (Table 1). A randomized phase II trial of first-line
ADT compared with platinum-based chemotherapy is
currently recruiting. Like prostate cancer, SDC develops
castrate resistance over time and the optimal second-line
treatment in this context is unknown. A recent phase II
trial of second-line abiraterone plus prednisone in ADT-
resistant patients showed an ORR of 21% with disease
control rate of 62.5% in 24 patients.57 Median PFS was
only 3.65 months with median OS 22.47 months. Other
areas of investigation include PSMA-targeted therapies as
described in an earlier section. Rarely, SDC will feature
mutations in TP53, PIK3CA, and HRAS/NRAS which
have not yet been evaluated as therapeutic targets.18
4.4 | Acinic cell carcinoma
Acinic cell carcinoma (AciCC) is typically a slow-growing
tumor with good prognosis but can undergo high-grade
transformation.97 The vast majority of patients are stage I
at diagnosis, and 10-year OS is 90%.98 Regional and distant
metastases are possible but uncommon, the latter typically
involving the lungs and brain. Local ablative treatments
including lymph node dissection, metastatectomy, and ste-
reotactic body radiation therapy can be considered for low
volume disease. Chemotherapy, when given, is typically
platinum-based, but there is no data to guide systemic
treatment. The majority of AciCC contain a t(4;9)(q13;q31)
rearrangement causing activation of NR4A3 which is
likely an oncogenic driver in this disease, although not yet
an actionable therapeutic target.99 Some tumors also
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demonstrate markers of activated mTOR signaling sug-
gesting a role for this pathway in tumorigenesis.100 In sup-
port of this, studies in xenograft models with inactivation
of both the PTEN and APC tumor suppressor genes
showed subsequent WNT and mTOR signaling activation
leading to the development of a malignant neoplasm that
morphologically represents human AciCC.100
4.5 | Secretory carcinoma
Previously known as mammary analog secretory carcinoma
(MASC), secretory carcinoma (SC) demonstrates genetic,
morphological and immunohistochemical resemblance to
secretory carcinoma of the breast.8,101 SC is a rare but indo-
lent neoplasm most often arising in the parotid gland.102,103
It typically has a good prognosis with 5- and 10-year
reported OS of 95%.104 Distant metastases can occur, most
commonly in the lungs, liver, and bones. There are no spe-
cific guidelines for treatment of SC, but data from AciCC is
often extrapolated given comparable growth patterns. Simi-
lar to SC of the breast, almost all salivary SC contain a
t(12;15)(p13;q25) translocation leading to the ETV6-NTRK3
fusion gene, which is highly specific for the SC histo-
type.8,105 ETV6-NTRK encodes a constitutively active tyro-
sine kinase targetable by TRK inhibitors such as
larotrectinib and entrectinib. In TRK-fusion positive can-
cers, larotrectinib yielded an ORR 80% among 12 patients
with SC in a phase II study.58 This was comparable to a
pooled analysis of phase I and II trials involving 159 solid
tumor patients treated with larotrectinib where objective
and complete responses were achieved in 79% and 16% of
patients, respectively.106 Entrectinib demonstrated a similar
ORR (86%) in seven cases of SC in an integrated analysis of
three phase I and II trials.59 Notably, patients with central
nervous system metastases were included in this study;
entrectinib may therefore be a preferred treatment for indi-
viduals with disease involving the brain or spinal cord. Lar-
otrectinib and entretinib have both received tissue-agnostic
FDA approval for tumors containing an NTRK fusion.
4.6 | RET-driven salivary gland cancers
A minority of diverse SGC histologies harbor activating
MET and RET fusions.107,108 The ARROW and
LIBRETTO-001 studies convincingly demonstrated the
durable efficacy of selective RET inhibitors pralsetinib
and selpercatinib, respectively, in RET-altered thyroid
and non-small-cell lung cancers.109–112 Early data regard-
ing the benefit of pralsetinib in other RET fusion-positive
histologies showed an ORR of 53% with median duration
of response 19 months, including a response in one
patient with SDC.113 Similarly, the tissue-agnostic benefit

WEAVER ET AL.
F I G U R E 1 Approach to treatment for recurrent/metastatic salivary gland carcinoma. Treatment options are listed in order of preference
where multiple options are available. ACC, adenoid cystic carcinoma; AR, androgen receptor; EGFR, epidermal growth factor receptor;
HER2, human epidermal growth factor receptor; NTRK, neurotrophic tyrosine receptor kinase; SBRT, stereotactic body radiation therapy;
TKI, tyrosine kinase inhibitor; TMB-H, tumor mutational burden-high.
of selpercatinib was confirmed in a cohort of 45 patients
with other locally advanced or metastatic RET fusion-
positive solid tumors, including four with salivary gland
carcinoma, with an ORR of 44% and median duration of
response over 2 years.114 Both drugs have been granted
FDA approval in RET-driven thyroid and lung cancers
but should also be considered for use in patients with
RET fusion-positive SGC.
5 | C ONCLUSIONS A ND F UTURE
DIRECTIONS
Salivary gland carcinoma is a diverse subgroup of head
and neck cancer which has frustrated medical oncologists
for decades due to lack of response to cytotoxic chemo-
therapy and immune checkpoint inhibition. Increased
genomic testing has revealed a tumor landscape rich in
potentially targetable molecular alterations, but the lack
of disease-specific randomized controlled trials continues
to be a barrier to the development of systemic therapy
guidelines in the inoperable and metastatic disease set-
tings. Our approach to treatment is summarized in
Figure 1, noting the general lack of head-to-head compar-
ison studies and resulting reliance on expert opinion.
These recommendations are contingent on expert pathol-
ogy review at a high- volume center due to the difficulty
in establishing an accurate diagnosis based on morphol-
ogy alone. An added benefit of the molecular profiling
reviewed here is the use of genetic alterations to confirm
pathologic diagnosis with seven SGC entities now defined
by tumor-specific genetic testing.115
As disease incidence is a limiting factor in the SGC
clinical trial space, a unified approach to the employment
10970347, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hed.27307 by University Degli Studi Di Tori, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
7
of this resource is essential. Importantly, an optimal strat-
egy may require re-evaluation of the best way to cohort
patients. The most recent update from the World Health
Organization classification of salivary gland tumors con-
tinued a trend of re-drawing the lines classifying disease
subtypes, making it difficult to establish historic treat-
ment controls. In cases where molecular alterations are
shared across subtypes, it is unclear whether patients are
best categorized by genetic profile, histology, or both,
reinforcing that the latter may result in vanishingly rare
groups. Many of the identified therapeutic targets are
seen in other cancers with higher incidence rates, so
extrapolation of tissue-agnostic data could provide a foun-
dation for strategic clinical trial design. The best example
of this is in HER2-positive SGC where the sequencing of
HER2-targeted therapies has largely been driven by expe-
rience in breast cancer. Somewhat unique to SGC is the
presence of multiple molecular alterations within the
same tumor, and it is unclear how this will impact
response to targeted therapy. For instance, does simulta-
neous overexpression of HER2 and AR mitigate efficacy
of either treatment in SDC? And, if so, how important is
the sequence in which HER2- and AR-targeted therapies
are given? These questions are less easily answered by
data from other disease types, and the rarity of any indi-
vidual molecular SGC subgroup remains a major con-
straint on the acquisition of prospective data.
Another challenge in designing prospective trials for
SGC is the indolent biology of many histiotypes, includ-
ing ACC. In a single-arm trial, can a stable disease
response be attributed to drug effect when the natural
history of untreated disease may not include RECIST-
measurable growth? This becomes especially important
with the prevalent use of molecularly targeted therapies

8 WEAVER ET AL.
which can produce meaningful anti-tumor responses
without causing significant shrinkage. One possible solu-
tion is to add RECIST-measurable progression within 6–
12 months of enrollment as an inclusion criterion. This
provision may capture a subset of more rapidly growing
disease, but the required consistency in pre-trial imaging
could be a significant barrier to accrual. Another option
is the addition of tumor growth kinetics to treatment out-
come measurements. For example, several groups have
assessed the impact of tumor growth rate (TGR), the
change in RECIST sums of target lesions over the time
between imaging assessments compared between refer-
ence and experimental time periods, on the determina-
tion of therapeutic benefit in phase I trials.116 In one
study, 82% of patients with stable disease by RECIST at
the first tumor evaluation actually had a significant
decrease in TGR, and TGR was independently associated
with PFS in multivariate cox regression analysis.117 This
method needs further validation but may provide added
value in preventing prolonged exposure to ineffective
therapy in more indolent disease types.
A final point of consideration is the use of immuno-
therapy in the treatment of SGC. While these tumors
have been resistant to PD-1 blockade alone, the impact of
checkpoint inhibition combined with chemotherapy, tar-
geted therapy, or another immunotherapy is unknown.
Studies to better define the immune microenvironment
in SGC are needed to identify alternate mechanisms for
immune modulation that may be more effective. In addi-
tion, the translational data from the ongoing
NCT03740256 and NCT04249947 CAR-T trials are
eagerly anticipated to further guide the use of cell ther-
apy in the treatment of SGC.
FUNDING INFORMATION
The authors received no financial support for the
research, authorship, and/or publication of this article.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new
data were created or analyzed in this study.
ORCID
Alice N. Weaver https://orcid.org/0000-0002-9398-1471
Daniel W. Bowles https://orcid.org/0000-0003-1406-
0963
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How to cite this article: Weaver AN, Lakritz S,
Mandair D, Ulanja MB, Bowles DW. A molecular
guide to systemic therapy in salivary gland
carcinoma. Head & Neck. 2023;1‐12. doi:10.1002/
hed.27307