EGFR in cervical cancer

Study to evaluate EGFR Status in Cervical Cancer

Dr. Lokesh Viswanath M.DProfessor, Dept of Radiation OncologyKidwai Memorial Institute of Oncology

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

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

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. 

Primary Objective: To evaluate EGFR Status in Cervical Cancer

Objective of the Study

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

Results

%IIB 30.7IIIB 53.8

IVA 15.3

Ca Cx Stage

Ca Cx Stage

Ca Cx Stage

432

Pe

rce

nt

60

50

40

30

20

10

0

Cx Primary Tumour Size

Primary Size Mean (cms) Std. Deviation

Length 5.35 +1.02

width 4.54 +1.12

Dense Bilateral Parametrial Disease upto lateral Pelvic Wall

Parametrium

Parametrium

20

Pe

rce

nt

100

80

60

40

20

0

Tumour GradeSCC Grade

SCC Grade

321

Pe

rce

nt

60

50

40

30

20

10

0

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:

EGFR Expression in % Cells Frequency Percent

< 24 % 2 8%

>25 – 95 % 23 92%

EGFR Expression inCervical Cancer Tumor Cells

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%

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

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

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

Review of Literature

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

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

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

Maartje G et al, 2009, Netherlands

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

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+. 

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

D D Meira et al, mechanisms of sensitisation of Cervial Cancer by EGFR inhibor C225

Emerging Interesting Clinical Data

Erlotinib - a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR)

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

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.

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

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.

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.,

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

Thank You