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Update on new treatments for recurrent cervical
cancer
Ursula Matulonis, M.D.
Associate Professor of Medicine, Harvard Medical School
Director/Program Leader, Medical Gynecologic Oncology
Dana-Farber Cancer Institute
Boston MA
Email: [email protected]
Agenda
Discuss new treatments for recurrent cervical
cancer:
--available therapies
--biologic agents and new therapies based on
rationale signaling pathway aberrations
Cervical Cancer
• Cervical cancer is the second leading cause of
cancer deaths among women worldwide.
275,000 women die from it annually.
• Only 10-20% of patients with recurrent or
advanced disease survive 5 years, despite
treatment.
• Urgent need to develop new therapies.
Jemal A, et al., CA Cancer J Clin, 2011
Chemotherapy for
recurrent cervical cancer
• Chemotherapy agents with activity in recurrent
cervical cancer:
platinum (carboplatin, cisplatin)1,2
platinum doublets3,4,5
Paclitaxel6
Ifosfamide7
Topotecan8
Others: gemcitabine, VP-16, altretamine
• Equivalency of carboplatin and cisplatin9,10
1Bonomi
et al, JCO 1985, 2ASCO 2012
3Long et al, JCO 2005,4 Moore et al, JCO 2004, 5GOG 204, 6McGuire et al, JCO 1996, 7Sutton et al,
Am J Obstet Gynecol 1993, 8Muderspach, Gyn Onc 2001, 9Kitagawa et al, ASCO 2012, 10Moore et al,
Gyn Onc 2007
Biologic agents tested in
cervical cancer
• Anti-angiogenics
Bevacizumab1
Sunitinib2
Pazopanib3
• EGFR inhibitors
Cetuximab4,5
--alone and in combination with cisplatin
Gefitinib
Erlotinib
-- alone and in combination with cisplatin6,7
• PDGFR inhibitors
Imatinib8
• Others
Monk et al, JCO 2009, Mackay et al, Gyn Onc 2011
celebrex
Monk et al, JCO 2010 Santin et al, Gyn Onc 2011
1
3
5Farley
2
4
et al, Gyn Onc 2011, 6Schilder et al, Int J Gynecol Cancer 2009
7Ferreira et al, ASCO 2008, 8Candelaria et al, Int J of Gyn Cancer, 2009
Bevacizumab in recurrent
cervical cancer
Overall RR 11% and 6 month PFS rate of 24%
Monk et al, JCO 2009
Pazopanib vs Lapatinib
versus combination
• 230 pts with recurrent cervix cancer
• 1:1:1
1) pazopanib 800 mg PO daily
2) lapatinib 1500 mg PO daily
3) combination (pazopanib 400/lapatinib 1000
or pazopanib 800/lapatinib 1500);
Combination arm eventually dropped
• Primary endpoint: PFS
Monk et al, JCO 2010
Results:
PFS 18.1(P) vs 17.1(L) weeks
Monk B J , Pandite L N JCO 2011;29:4845-4845
GOG 204
Topotecan 0.75 mg/m2 IV
days 1,2,3 and cisplatin 50 mg/m2
IV day 1 cycles repeated q 3 weeks x 6*
Eligibility:
•measurable disease
•GOG performance status
0-1
•ANC ≥ 1500/mcl
Paclitaxel 135 mg/m2 IV over
24 hours and cisplatin
•platelets ≥100,000/mcl
Primary Stage IVB or
50 mg/m2 IV day 1
•serum creatinine <1.5
recurrent/persistent
cycles repeated q 3 weeks x 6*
mg/dl
carcinoma of the cervix
•no CNS disease
Vinorelbine 30 mg/m2 IV days 1 •no past or concomitant
and 8
invasive
cisplatin 50 mg/m2 IV day 1
cancer
cycles repeated q 3 weeks x 6
•no prior chemotherapy
(unless concurrent
Gemcitabine 1000 mg/m2 IV, days
with radiation)
1 and 8 along with
cisplatin 50 mg/m2 IV day 1
cycles repeated q 3 weeks x 6
N=513
JCO 2009
GOG 204
GOG 204 conclusions:
VC, GC, and TC are not
superior to PC in terms of
overall survival (OS).
However, the trend in RR, PFS,
and OS favors
Paclitaxel/cisplatin
Differences in chemotherapy
scheduling, pre-existing
morbidity, and toxicity are
important in individualizing
therapy.
GOG 240
Does addition of bevacizumab to chemotherapy
improve efficacy and does a non-platinum doublet
have efficacy in advanced cervical cancer?
Eligibility:
• Primary Stage IVB or recurrent/persistent carcinoma
of the cervix
• Measurable disease
• GOG performance status 0-1
GOG 240
Paclitaxel +
cisplatin
Eligibility
confirmed
Primary Endpoints:
• Overall survival (OS)
• Frequency and severity of
toxicity
Secondary Endpoints:
• Progression-free survival
(PFS)
• Tumor response
Paclitaxel +
cisplatin +
bevacizumab
Paclitaxel +
topotecan
Paclitaxel +
topotecan +
bevacizumab
Opened: 4/6/2009
accrual met 450 pts.
Identification of molecular
alterations in subtypes
• Epidemiological shift in cervical cancer: squamous
cell cancers (SCC) decreasing and adenocarcinomas
(AC) rising from 5%24%.
• AC worse prognosis: 10-20% lower 5-year OS, and
higher rates of local and distant spread.
• Currently SCC and AC are treated similarly.
Wang SS, et al., Cancer, 2004; Gien LT, et al., Gynecol Oncol, 2010.
A Paradigm Shift: The Genomic View of Cancer
Slide courtesy of Levi Garraway
Reported Alterations
in Cervical Cancer
1
Gene
EGFR 1,2
Sample
n=89
n=111
Reported
No mutations (exons 19 and 21)
No mutations; 10.2% SCC had amplification
PIK3CA 3,4
n=14
n=40
36% SCC mutations
70% amplification
KRAS 5,6
n=47
n=258
6.3% mutations
0.7% SCC and 13.9% AC
HRAS/NRAS 7
n=9
No mutations; increased gene expression
STK11 (LKB1) 8
n=86
9% deletions and mutations
BRAF 5,6
n=47
n=258
No mutations
0.0% SCC and 4.3% AC
1Arias-Pulido
H, Int J Gynecol Cancer, 2008; 2 Iida K, Br J Cancer, 2011; 3Janku F, PLoS One, 2011, 4 Bertelsen BI, Int J
Cancer, 2006; 5 Pappa KI, Gynecol Oncol, 2006; 6 Kang S, Gynecol Oncol, 2007; 7 Mammas IN, Gynecol Oncol, 2004; 8
Wingo SN, PLoS One, 2009.
Genomic analysis reveals
PI3K pathway mutations
in cervical cancer
Key components of the
PI3kinase pathway:
RTK
AKT
PI3K
PTEN
mTORC2
mTORC1
Many other targets that regulate:
Growth, energy utilization and cell
survival
Receptor tyrosine kinase
PI3kinase
PTEN
AKT, mTORC1 and 2
Study Aims
1) Describe the most common oncogenic
mutations in cervical cancer.
2) Compare the type and frequency of somatic
mutations present in cervical AC versus SCC.
3) Identify novel therapeutic targets.
Wright, ASCO 2012
“OncoMap” Strategy for Profiling
Known Genomic Mutations
• Archival tumor samples examined by a gynecologic oncology
pathologist. Areas >80% tumor cored and DNA extracted.
• Tumor-derived DNA was subjected to whole genome
amplification, and multiplexed PCR was performed to amplify
regions harboring loci of interest.
• Primer extension products were spotted onto a specially
designed chip and analyzed by MALDI-TOF mass spectrometry
to determine the mutation status.
• Results were validated by hME with unamplified tumor DNA.
• Examined 1284 mutations in 172 genes.
• Also examined PTEN loss by immunohistochemistry.
Thomas et al., Nature Genetics, 2007; MacConaill et al., PLoS One, 2009;
and Dias-Santagata et al., EMBO Mol Med, 2010.
Patient Characteristics (n=78)
Age, mean (SD)
Race
White
Black
Other
Histology
Adenocarcinoma
Squamous cell carcinoma
Stage
IA2
IB1
IB2
IIA
IIB
IIIB
IV
Grade
Well differentiated
Moderately differentiated
Poorly differentiated
44.5 (11.0)
63 (80.8%)
9 (11.5%)
4 (5.1%)
41 (52.6%)
37 (47.4%)
11 (14.1%)
34 (43.5%)
2 (2.6%)
8 (10.2%)
13 (16.7%)
5 (6.4%)
5 (6.4 %)
23 (29.5%)
32 (41.0%)
21 (21.8%)
Wright, ASCO 2012
Results
• 43/78 (55.1%) of cervical cancer specimens
harbored candidate mutations.
• 6/78 (7.7%) had ≥2 co-mutations. 5/6 of these
had co-mutations in exon 9 of PIK3CA; only 1
sample had coexisting PIK3CA and KRAS
mutations.
• 3/48 (4.9%) had evidence of PTEN loss on
immunohistochemistry (both AC and SCC).
Wright, ASCO 2012
High Rates of PIK3CA Mutations
in Both AC and SCC
E545K
Mutations
Overall n=78
E542K
AC (n=41; 32%)
SCC (n=37; 35%)
E453k
P=0.47
R88Q
0
2
4
Patients
6
8
Wright, ASCO 2012
KRAS Mutations
Detected in AC Only
Mutations
G12A
Overall n=78
G12D
AC (n=41; 17%)
SCC (n=37; 0%)
G12V
P=0.004
G13D
0
1
2
3
Patients
Wright, ASCO 2012
Clinical Correlations
• We did not observe any associations between
validated mutations and patient characteristics:
– Stage, grade, tumor size
– Lymph node involvement
– Disease free survival
– Overall survival
• Limited by small sample size, low frequency of
events, and short follow-up time (median 27
months).
Wright, ASCO 2012
Conclusions of mutational data
• First report of a high throughput mutational
analysis of cervical cancer.
• Data revealed distinct genomic alterations in
SCC and AC; KRAS mutations found in AC and
PIK3CA mutations found in SCC.
• This data supports the importance of further
studies to better understand these mutations
and exploit them for clinical use.
Wright, ASCO 2012
Conclusions: Overall
• Cervical cancer is the 2nd leading cause of
cancer death in the world.
• Existing treatment for recurrent cancer has
little effectiveness
• Newer therapies are needed
Aberrant signaling pathways
Immunologic therapies