Transcript Adenoid Cystic Carcinoma: A clinical and molecular review

Adenoid Cystic Carcinoma: A
clinical and molecular review
Patrick Ha, MD FACS
Associate Professor, Johns Hopkins Department of Otolaryngology
Johns Hopkins Head and Neck Surgery
GBMC Head and Neck Grand Rounds, November 1, 2013
Disclosures
• Research Funding:
– NIH/NIDCR
– Champions Oncology
– Adenoid Cystic Carcinoma Research
Foundation
Adenoid cystic carcinoma
Of all tumors in the region of the head and neck,
the adenoid cystic carcinoma is one of the most
biologically deceptive and frustrating in
management. The subtlety of its presence,
masquerading often as a benign tumor for years,
the unexpected pernicious extensions, the high
incidence of local recurrence and systemic
spread, and the temporary favorable response to
irradiation usually lead on the pathway to death.
- John Conley
Adenoid Cystic Carcinoma
• Second most common salivary gland
malignancy
• Age: 40-50
• Women > men 3:2
• No associations with known exposures or
diseases
• 50% present with pain
• Minor salivary glands > submandibular >
parotid
Numbers
• Disease free survival: 60%, 50% 45%
• Cause specific survival: 80%, 65%, 50%,
40%
• 25-50% metastatic rate
• Time to metastasis: 36 months (1mo – 19yrs)
• Survival after metastasis: 40%, 15%, 10%
(isolated pulmonary metastasis > bony mets)
Spiro RH, Am J Surg 1997;174(5):495-8
Pathology
• Cribriform (swiss
cheese)
• Tubular
• Solid
Perineural Invasion
Surgical approach
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Wide local excision
Neck dissection (?)
Clear margins
Balance with functional outcome
Nerve preservation when possible
Metastatectomy
Surgical approach
• “the biggest operation that can be rationally
developed is the best” (Conley 1974)
• Casler and Conley (1992) espoused radical
parotidectomy for T2-3 lesions
• No difference in survival with radical surgery
• Obtain clear margins when feasible, balance
with functional outcome
• Elective lymph node sampling low yield
Metastatectomy
• Locati et al (2005) performed 26
procedures
• If clear margins, then improved freedom
from progression
• No benefit to survival shown
• Liu et al (1999) – pulmonary resection
did not cure patients
• Still performed in some centers
Peter Tork
Radiotherapy
• No prospective randomized controlled study
• Doses >60Gy more effective
• Not effective as primary treatment (may have
palliative role)
• Appears to be good for local control in
adjuvant setting
• ?effect on survival
• Retrospective bias
Garden AS et al, Int J Radiation Oncol Biol Phys 1995
Garden AS et al, Int J Radiation Oncol Biol Phys 1995
Neutron Beam Therapy
• Reduced cell damage repair, less variation
during cell cycle, less oxygen requirements
• 1988 – RTOG study found neutron beam
better at local control and trend towards
survival1
• Douglas et al2 – 159 patients with
unresectable or gross+ margins. 5 yr survival
77%.
1Laramore
2Douglas
GE et al. Int J Radiat Oncol Biol Phys. 1993;27(2):235-40
JG et al, Int J Radiat Oncol Biol Phys. 2000;46(3):551-57
Laramore et al. Int. J. Radiat. Biol. Phys. 27: 235-240, 1993
Their conclusion
• “Further improvements in local-regional
control are not likely to impact survival
until more effective systemic agents are
developed to prevent and/or treat
distant metastatic disease.”
2Douglas
JG et al, Int J Radiat Oncol Biol Phys. 2000
Neutron therapy and ACC
Huber PE et al. Radiotherapy and Oncol 2001;59(2);161-67
Neutron therapy and ACC
Huber PE et al. Radiotherapy and Oncol 2001;59(2);161-67
• Neutron beam less used recently
• Follow up studies not as favorable
• Toxicity level much higher
• Investigators looking at carbon ions (Phase II)
• ACCEPT - Cetuximab, IMRT with C12 heavy ion
boost) for recurrent disease.
• COSMIC – IMRT with C12 boost
Adam Yauch (MCA)
Role for Chemotherapy in ACC
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ACC needs systemic control
Many limited trials performed
Difficult to quantify response
Limited numbers of patients – can one
use the same agents across
histologies?
• Chemotherapy versus targeted therapy
Important Guidelines in ACC
Trial Evaluation
• Evaluate rationale for use of known
drugs in ACC: molecular basis for
therapy
• Enrollment criteria – recurrent vs
progressive vs metastatic
• Adherence to RECIST criteria reporting
Single Agent Chemotherapy
Trials
Papaspyrou et al, Head Neck, 2011:33:905-11
Molecular targets in ACC
• cKIT – growth, differentiation and migration.
Expressed highly in 100% of ACC. No
mutations found. May not be phosphorylated
(activated) in ACC
• EGFR – proliferation, motility, adhesion,
invasion, angiogenesis, survival. 0-85%
expression in ACC
• Her-2 – 0-100% in ACC.
Liu J et al, Head Neck, 2011
More molecular targets…
• VEGFR – angiogenesis. Independent
prognostic factor in salivary gland
carcinoma. Cell line studies performed*
• NFkB – suppresses apoptosis,
regulated VEGF - ubiquitin-proteasome
degradation pathway.
The c-kit story
• Identified as a tyrosine kinase receptor
in 1987
• Proto-oncogene, found in testicular
tumors, AML, GI stromal tumors, ACC
• Found in a high percentage of ACC
(Jeng et al, 2000, Freier et al 2005)
• Loss of function: deafness, pigment
defects
C-Kit Pathway
Imatinib
• Blocks abl, c-kit, PDGF-R
• Imatinib used in 2 patients with unresectable
disease with + response (Alcedo et al 2004)
• Formal multicenter trial – 16 patients with
unresectable disease (Hotte et al, 2005)
• No objective measures of response
• 9/16 patients with stable disease
• 6 patients with progressive disease
• Separate trial with 10 patients also closed
(Pfeffer et al, 2006)
A decade of trials
www.accrf.org
Lapatinib
• ErbB2 and EGFR inhibitor
• Recurrent, progressive, or metastatic
disease tested for 1+ EGFR and/or 2+
ErbB2
• 29/33 patients met criteria, 19
assessable patients treated
• No objective response, 15 with stable
disease (9 with stable disease >6
months), 4 with progressive disease.
Agulnik M et al, JCO 2007 25(25):3978-84)
ECOG 1303: Bortezomib +
doxorubicin
• Bortezomib – inhibitor of NFkB and 26S
proteasome
• If progressed, added doxorubicin
• 24 patients received tx, no objective
response with bortezomib – stable dz in
15/21. 10 had both D+B, 1 partial
response, 6 stable disease
• Well tolerated, but no response noted
Argiris A et al, Cancer 2011, Aug 1; 117(15):3374-82
Sunitinib
• Target VEGF, c-kit, RET, FLT3
• Progressive, recurrent and/or metastatic
ACC
• 13 assessable patients – no objective
response. 11 with stable disease (8>6
months), 2 patients had progression.
Chau NG et al. Ann Oncol 2011
Cetuximab and Cis-platinum
• Locally advanced* (n=9) or metastatic
(n=12) with positive EGFR expression
• Loaded with Cetuximab, followed by
weekly infusion
• Locally advanced tumors received
radiation and cisplatin
• Metastatic received cis-platin and 5-FU
* Refused surgery or unresectable
Hitre E, et al. BJC 109, 2013
• Local advanced disease (n=9):
– PFS = 64 months
– 2-yr OS =100%
– 2 CR, 2 PR, 5 SD
• Metastatic (n=14):
– PFS = 13 months
– 2-yr OS = 24 months
– 5 cases of PR
Hitre E, et al. BJC 109, 2013
Current Trials
• Eribulin Mesylate in recurrent or
metastatic salivary gland cancer
– Phase II. Microtubule inhibitor. Most
studies in breast cancer
• RTOG 1008: radiation therapy +/- cisplatin in advanced salivary gland
cancers
• Dovitinib
Ways to improve trials
• Consider symptom improvement
• Include survival statistics
• Include progressive or symptomatic
patients only and describe criteria
• Consider previous therapies and
number/site of recurrence
• Report ACC results separate from other
salivary tumors
Laurie SA et al, Lancet Oncology, 2011:12;815-24
John McCain
Myb-NFIB fusion gene
• NFIB – human nuclear transcription
factor (9p23-24)
• MYB – oncogene – cell proliferation,
apoptosis, differentiation. (6q22-23)
Persson et al, PNAS, 2009: 106(44): 18740-44
Implications of Myb-NFIB
Fusion Gene
• Myb-NFIB fusion present in 28-49% of ACC
• Very specific for ACC, not other SGTs
• Majority of ACC showed Myb overexpression,
but higher levels if fusion present
• Fusion may be variable
• Unclear prognostic significance – high Myb
expression and/or fusion gene may suggest
worse outcome
West RB et al, Am J Surg Pathol, 2011:35(1):92-9
Mitani Y et al. Clin Cancer Res, 2010;16(19):4722-31
MYB
• No drug specifically targeting MYB yet
• Possible downstream targets:
– Cell cycle control (CCNB1, CDC2,
MAD1L1)
– Apoptosis (API5, BCL2, BIRC3, SHPA8,
SET)
– Cell growth/angiogenesis (MYC, KIT,
VEGFA, FGF2, CD53)
Exome Sequencing
• Low mutational rate
• Confirmed Myb translocations
• Implicated FGFR pathway (3/24 and
30%), chromatin regulation
• Underwhelming overall
Ho AS et al. Nature Genetics, 2013
Stephens PJ et al, JCI, 2013
Dovitinib
• FGFR1 is over-expressed (1a) and
phosphorylated (1b) in the
preponderance of ACC tumors.
• FGF2, a molecule that binds to FGFR1,
is a known downstream target of MYB
• Screened in several xenograft mouse
models of ACC and demonstrated
activity
Dovitinib Trial
• Recurrent or metastatic disease
• Phase II – endpoint = survival
• Orally dosed – 500 mg, 5 days on, 2
days off for 4 weeks.
• Treatment continues
• 10 accrued in Uva, open enrollment for
33 in Korea
Other Possibilities?
• Personalized medicine approaches
– Identification of specific known tumor
markers
– Xenograft model creation
• In vivo testing for predictive tumor behavior
• Identification of novel personal markers
• Molecular profiling for identification of
newer drug-able targets
Moskaluk CA et al, Lab Invest, 2011:91(10);1480-90
Conclusions
• Difficult tumor to treat when recurrent or
metastatic, which is common
• Surgery + radiation are standard
• Numerous clinical trials, but limited
conclusions drawn
• Supports enrollment in clinical trials
• Hope for molecular discovery leading to
newer rational targets
Irwin Jacobs
ACCRF