the magnitude of over expression of EGFR in cervical cancer is not known

1. Dr. Lokesh Viswanath M.D
Professor, Dept of Radiation Oncology
Kidwai Memorial Institute of Oncology

2.  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

3.  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.

4.  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.

5.  Primary Objective: To evaluate EGFR Status in
Cervical Cancer

6.  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

8. %
IIB 30.7
IIIB 53.8
IVA 15.3

9. Ca Cx Stage
Ca Cx Stage
2 3 4
Percent
60
50
40
30
20
10
0

10. Primary Size Mean (cms) Std. Deviation
Length 5.35 +1.02
width 4.54 +1.12

11. Parametrium
Parametrium
0 2
Percent
100
80
60
40
20
0

12. SCC Grade
SCC Grade
1 2 3
Percent
60
50
40
30
20
10
0

13. 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

14. EGFR Expression in
% Cells Frequency Percent
< 24 % 2 8%
>25 – 95 % 23 92%

15. Tumor Cell Cytoplasmic and nuclear positivity
for EGFR antibody
+ve Uptake of EGFR
Antibody Frequency %
Negative 2 8
1+ 9 36
2+ 6 24
3+ 8 32
Occasional Nuclear +vity 7 30%

16. Pre RT(cms) Post RT (cms) EGFR %
6x5 6x4 90
5.5x5 3x2 95
5x3 3x2 95
Width
Length
6
4
2
0
Pre RT
Post RT
Width
Length

17.  A preliminary assessment in Cervical Cancer at
50Gy shows persistent residual disease i.e, <
50% response (PR) in Subjects with high EGFR
expression

18.  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

20.  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

21. 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

22.  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).

24.  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.

25.  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+.

27.  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:

29.  Emerging Interesting Clinical Data

30.  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%)

31.  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.

32.  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

33.  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).

34.  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

35.  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

36. Thank You