egfr in cervical cancer
DESCRIPTION
the magnitude of over expression of EGFR in cervical cancer is not knownTRANSCRIPT
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Study to evaluate EGFR Status in Cervical Cancer
Dr. Lokesh Viswanath M.DProfessor, Dept of Radiation OncologyKidwai Memorial Institute of Oncology
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Dr. Chetana Basavaraj Dr.Naveen T, Dr.SiddannaPallade Dr.P.Siridahar Dr.Bindhu Joseph Dr.TanveerPasha Dr.K.P.Jagannath Dr.K.P.R.Pramod Dr.Asha Latha Dr.Priya Dr.Ashwini Dr.Anil
Study Team
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EGFR is expressed at low levels in most normal epithelial tissues and is predominantly associated with squamous cell carcinoma.
EGFR is overexpressed in tumors of SCCHN
(>90%),breast(25%), lung, brain, bladder, gastric, esophagus, cervix, ovary and endometrium.
Introduction
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The magnitude to which EGFR is over expressed in Cervical Cancer is not known
Currently, expression of EGFR as a biomarker for prognosis or for treatment of cervical cancer is not defined for clinical use.
There is very scant experimentation on EGFR inhibition in cervical cancer cell lines.
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Primary Objective: To evaluate EGFR Status in Cervical Cancer
Objective of the Study
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Proved Cancer Cervix – Treatment naïve n = 25 Mean age : 51 + 10.6yrs Clinical Examination : PS/PV/PR Investigations:
◦ Punch Biopsy – Formalin Container ◦ Routine : Hemogram , Biochem – RBS,RFT,LFT◦ Chest X Ry – PA View◦ U/s Abd & Pelvis◦ CT scan – Pelvis◦ Optional - Cystoscopy / Sigmoidoscopy
Treatment : ◦ Radical Radiation Therapy (Ext RT 50Gy/25f/5fr/wk + HDR I/c
Brachytherapy)◦ with RT Sensitizer weekly CDDP
Response Assessment: PS/PV/PR / CT Scan pelvis◦ End of Ext RT , 3month Post RT, 6 mo Post RT , 1yr
Material & Methods
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Results
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%IIB 30.7IIIB 53.8
IVA 15.3
Ca Cx Stage
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Ca Cx Stage
Ca Cx Stage
432
Pe
rce
nt
60
50
40
30
20
10
0
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Cx Primary Tumour Size
Primary Size Mean (cms) Std. Deviation
Length 5.35 +1.02
width 4.54 +1.12
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Dense Bilateral Parametrial Disease upto lateral Pelvic Wall
Parametrium
Parametrium
20
Pe
rce
nt
100
80
60
40
20
0
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Tumour GradeSCC Grade
SCC Grade
321
Pe
rce
nt
60
50
40
30
20
10
0
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Immunohistochemistry 5 micron sections Monoclonal primary antibody murine ioR3
(1:50 dilution) EGFR expression Evaluation: Cytoplasmic
and Nuclear Positivity for EGFR antibody EGFR expression in % of Tumor Cells
Tumor EGFR Expression:
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EGFR Expression in % Cells Frequency Percent
< 24 % 2 8%
>25 – 95 % 23 92%
EGFR Expression inCervical Cancer Tumor Cells
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Tumor Cell Cytoplasmic and nuclear positivity for EGFR antibody
+ve Uptake of EGFR Antibody Frequency %
Negative 2 81+ 9 362+ 6 243+ 8 32
Occasional Nuclear +vity 7 30%
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Post RT (50Gy)Response AssessmentPre RT(cms) Post RT (cms) EGFR %
6x5 6x4 905.5x5 3x2 955x3 3x2 95
Pre RT
Post RT
0
1
2
3
4
5
6
Width
Length
WidthLength
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Clinical observation
A preliminary assessment in Cervical Cancer at 50Gy shows persistent residual disease i.e, < 50% response (PR) in Subjects with high EGFR expression
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EGFR Expression in Cervical Cancer Tumor Cells is 92%
Pointers > Subjects with High EGFR expression have poor response to RT
followup the study subjects for Survival analysis
There is a need for greater interest in use of Biologic agents targeting EGFR in Cervical Cancer along with RT+CT
Conclusion - preliminary
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Review of Literature
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Subjects with High EGFR expression are known to have poor prognosis in SCCHN
EGFR inhibitors have proven efficacy in some clinical trials in patients with cancers of head and neck, lung, colon, pancreas etc
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Cervical cancers: Retrospectively evaluated & reported
EGFR receptor is over expressed in 70-90% of
cervical cancer EGFR over expression independently predicts poor
prognosis in cervical cancer patients, which makes it a potential therapeutic target
Schrevel M et al, 2011
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cervical cancer n= 375 stage Ib to IVa patients Treated with chemo-radiation January 1980 and December 2006. Clinico-pathologic and follow-up data - evaluated
Observation: EGFR staining was present in 35.3%, pEGFR in 19.7% membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-
2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P =
0.016) were independent predictors of poor response to (chemo)radiation.
Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014).
Maartje G et al, 2009, Netherlands
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Maartje G et al, 2009, Netherlands
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n=53 Ca Cx EGFR overexpression
◦ primary cervical tumors (2+ or 3+) - 64%◦ corresponding lymph node metastases -60%
Observation:◦ The EGFR expression seems to be common
and stable during cervical cancer metastasis, which is encouraging for testing of EGFR targeted radiotherapy.
◦ HER2 appears to be of poor interest as a potential target in the treatment of cervical cancer.
Li Shen et al, 2008
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Comparisons of immunohistochemical EGFR staining of primary cervical carcinoma (A) and corresponding metastases (B).
Both A and B (from the same patient) were scored 3+.
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cervical cancer cells lines Enhancement of Radiation Sensitivity
by EGFR inhibitors Combination
◦ C225 (cetuximab) + CDDP + Radiation (0.3, 1.5, 2 Gy exposure)
◦ Trastuzumab◦ MAPK inhibitors:
In Vitro Experiments
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D D Meira et al, mechanisms of sensitisation of Cervial Cancer by EGFR inhibor C225
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Emerging Interesting Clinical Data
Erlotinib - a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR)
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PATIENT CHARACTERISTICS• N=36 Patients entered in the study• Median age: 45 (28-68)• Performance status: 0-2• Cell type: Squamous cell cervical carcinoma• Stage at diagnoses:
– IIB: ( 55%)– IIIA: (3%)– IIIB: (42%)
ERLOTINIB(E) COMBINED WITH CISPLATIN (C) AND RADIOTHERAPY (RT) FOR PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CERVICAL CANCER:A PHASE II TRIAL
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34 patients completed Erlotinib+CRT◦ Response was assessed after 3 month-MRI, CT,
PET-CT and Biopsy.
27 –evaluable patients:◦Completed Response: 25pts (92.6%)◦Partial Response: 2 pts ( 7.4%)
◦median follow-up of 13.8 months, none of the pts have progressed.
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Ca Cx Post RT/RT-CT - Failure Salvage Treatment with C225 + CDDP –
Some minor benefits Salvage Treatment with C225 + Topotecan+
CDDP – Toxic with Some minor benefits
No comparative arm
C225 Data
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September 2004 and March 2008 76 patients : Safety & efficacy analysis of C225 &
CDDP 69 were eligible and evaluable; 44 (64%) received prior chemotherapy. EGFR protein was expressed in 47/48 (98%) of tumors
analyzed with a median cellular expression of 81%. Five patients (14.3%) survived without progression for
at least 6 months. The median PFS was 3.91 months (95% CI 2.73 –
4.53) with a median OS of 8.77 months (95% CI 7.56 – 10.09).
Farley J et al. 2011. Phase II study of cisplatin plus cetuximab in advanced, recurrent, and previously treated cancers of the cervix a Gynecologic Oncology Group study.
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April and July 2007 Cp 50 mg/m(2) on day 1 plus Tc 0.75 mg/m(2)/day
from days 1 to 3 every 3 weeks combined with Ce (initial dose of 400 mg/m(2) followed by subsequent weekly dose of 250 mg/m(2))
19 out of the 44 planned (stopped early due to excessive toxicity)◦ 3-4 neutropenia (72%),◦ grades 3-4 thrombocytopenia (61%)◦ grade 3 anemia (44.5%).◦ Five (28%) patients died during the treatment ( 3 deaths -
treatment toxicity)◦ Six (32%) evaluable patients achieved a partial response. ◦ The median times of PFS and OS were 172 and 220 days
Kurtz JE et al, Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: A phase II GINECO trial.,
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Even though the C225 data is not encouraging
Erlotinib data proves that EGFR inhibitors have a greater role to play in Concurrent Chemoradiation setting
Concurrent Chemoradiation :◦ Nimotuzumab + CDDP + Radiation Therapy◦ Looks like an encouraging option based on SCH&N Study
experience ◦ Is expected to be less toxic than C225 ◦ Ongoing Clinical Trial on Ca Cervix with Nimotuzumab +
CDDP + Radiation Therapy - Data is not yet available
Conclusion
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Thank You