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Shivali
Jasrotia
1
2
EGFR is:
I. is a member of the family
of EGF- related TK
receptors.
II. expressed on normal
epithelial cells and on
malignant cell types
III. In NSCLC tumor cells,
EGFR is frequently over
expressed by 50% to 80%.
Introduction
3
4
EGFR can be shed from the cell surface and appears in the blood in soluble
form. It consists of a set of differently sized fragments of the extracellular
domains of the receptor generated mainly by alternate mRNA splicing or by
proteolytic cleavage.
5
Sandwich ELISA
 To investigate sEGFR concentration and to elucidate
its potential utility as a biomarker.
 To further correlate it with clinical, pathological, and
prognostic variables in a large cohort of 308 advanced
NSCLC patients.
Purpose of the study
6
Patients:
Retrospective study of 308 patients with NSCLC enrolled
b/w Feb 2003 and Jan 2005
Inclusion criteria:
1. Histological confirmed advanced NSCLC patients
2. Age >18 years
3. At least one disease measurable by the RECIST
4. ECOG PS 0 to 2 and adequate hematologic, renal,
and hepatic function
5. Informed consent provided by all individuals.
Patients and Methods
7
Exclusion criteria:
Active metachronous cancer, severe heart disease, active
infection, pregnancy, and other severe medical conditions.
Controls:
109 healthy volunteers without acute or chronic inflammatory
conditions.
Controls are collected during the same period as the patients
samples.
Patients and Methods
8
Treatment and Evaluation:
Patients with treated with cisplatin (75 mg/m2) and docetexal (75 mg/m2)
on day 1 every 3 weeks.
Patients were restaged for objective response after the first three cycles
of chemotherapy.
Patients progressing before or at first evaluation were shifted to a
second-line treatment.
Samples:
PB taken from individuals at baseline.
Centrifuged and plasma aliquots were taken for further study.
Patients and Methods
9
EGFR Quantification:
Plasma EGFR concentration was determined at baseline using
microtiter sandwich ELISA .
Patients and Methods
10
Statistical Analysis
Comparisons and correlations with categorical variables were conducted
using the Student’s t-test.
The association between categorical variables was evaluated using the χ2
test.
Performance of EGFR in the prediction of disease versus control status
was evaluated using the receiver operating characteristic (ROC) curve.
The univariate analysis (performed in parallel by KM and Cox methods)
were performed along with multivariate Cox analysis.
11
12
ROC Curve and AUC
ROC curve is a plot of sensitivity
versus 1- specificity
Sensitivities and specificities of a
test depend on the cut-off levels
that are used to define the positive
and negative test results.
Area under the ROC curve (AUC)
provides a measure of the overall
performance of a diagnostic test.
The closer AUC is to 1, the better the overall diagnostic performance of the test,
and a test with an AUC value is 1 then, the test is perfectly accurate.
13
Results
14
Plasma sEGFR concentration in Patients and Controls
Plasma sEGFR concentration found b/w both groups were statistically
different (mean±2 SEM: 30.98 ng/mL ± 0.82 vs 34.91ng/mL ±1.10, P<
.0001).
To evaluate the potential screening utility of sEGFR concentration, ROC
curves are generated to compare healthy controls to patients, thus
yielding an AUC of 0.341 (95% confidence interval [CI], 0.286- 0.397).
The best cut-off value for sEGFR to distinguish patients from controls
was 31.62 ng/mL, resulting in 80% sensitivity and 49% specificity.
This represents an acceptable specificity but a poor sensitivity, indicating
that baseline sEGFR is not a strong biomarker to discriminate NSCLC
patients from healthy controls.
15
Correlation with sEGFR conc. with clinical- pathological Variables
No correlations were observed between baseline sEGFR concentration and
gender, stage, PS, number of metastatic sites or locations of metastatic sites.
On evaluating the correlation b/w sEGFR and treatment response, the patients
with progressive disease (PD) had lower sEGFR compared with the others (CR,
PR, and SD), 30.23 ng/mL ± 1.38 vs 31.72 ng/mL ± 1.11, respectively.
A trend of higher sEGFR concentration in patients with ADC compared with SCC
was observed, but the differences were not significant (mean ± 2 SEM; 31.74
ng/mL ± 1.14 versus 30.19 ng/mL ± 1.44, respectively, P = .081).
Results
16
Correlation with sEGFR conc. with Survival
Patients with baseline sEGFR below the cut-off value (cut-off concentration of
34.56 ng/mL) displayed no significant difference in TTP compared with patients
with sEGFR above this value.
Patients with baseline sEGFR ≤34.56 ng/mL had a shorter OS compared with
other patients; median survival: 9.1 months (95% CI, 7.6-10.6) versus 12.2 months
(95% CI, 10.4-13.9); (P= .019).
The subgroup of patients with sEGFR ≤ 34.56 ng/mL had a worse prognosis but
was not significantly different from the other groups in the frequencies of histologic
types, PS, gender, or treatment response except differences for stage (borderline,
P= .071) and age (P= .003) between subgroups.
In the univariate analysis, only gender, PS, localization of metastasis (local versus
distant), number of metastatic sites, as well as sEGFR were significantly
associated with survival.
Results
17
18
19
20
21
22
Discussion
A significantly lower concentration of sEGFR in NSCLC patients than in
controls has been observed, although sEGFR is a sensitive (80%
sensitivity) but not specific (49% specificity) biomarker to distinguish
NSCLC patients from controls.
No correlations were observed between sEGFR concentration and other
well-established pathological features of advanced NSCLC.
Only the patients with PD tended to have lower sEGFR concentrations,
but this difference was not significant.
In metastatic breast cancer, several reports show that patients with
decreased concentrations of sEGFR have reduced survival whereas no
studies have yet assessed the utility of plasma sEGFR as a prognosticator
of NSCLC.
23
24
Conclusion
sEGFR is a useful prognostic biomarker in NSCLC patients.
Lower sEGFR concentration was related to a poorer prognosis.
Evaluation of this marker is needed in a prospective large-scale studies
as a predictor of response to chemotherapy-based treatments, anti-
angiogenic agents and TKIs.
The poorer prognoses observed may have multiple hypothetical
explanations:
(1) sEGFR in the blood binds the ligand quicker than EGFR.
(2) the low concentration of sEGFR may prevent the formation of sEGFR/
EGFR dimers which are capable of inhibiting the kinase activity by
acting as negative regulators of the EGFR signalling cascade
25
26

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EGFR Plasma concentration in lung cancer

  • 2. 2
  • 3. EGFR is: I. is a member of the family of EGF- related TK receptors. II. expressed on normal epithelial cells and on malignant cell types III. In NSCLC tumor cells, EGFR is frequently over expressed by 50% to 80%. Introduction 3
  • 4. 4 EGFR can be shed from the cell surface and appears in the blood in soluble form. It consists of a set of differently sized fragments of the extracellular domains of the receptor generated mainly by alternate mRNA splicing or by proteolytic cleavage.
  • 6.  To investigate sEGFR concentration and to elucidate its potential utility as a biomarker.  To further correlate it with clinical, pathological, and prognostic variables in a large cohort of 308 advanced NSCLC patients. Purpose of the study 6
  • 7. Patients: Retrospective study of 308 patients with NSCLC enrolled b/w Feb 2003 and Jan 2005 Inclusion criteria: 1. Histological confirmed advanced NSCLC patients 2. Age >18 years 3. At least one disease measurable by the RECIST 4. ECOG PS 0 to 2 and adequate hematologic, renal, and hepatic function 5. Informed consent provided by all individuals. Patients and Methods 7
  • 8. Exclusion criteria: Active metachronous cancer, severe heart disease, active infection, pregnancy, and other severe medical conditions. Controls: 109 healthy volunteers without acute or chronic inflammatory conditions. Controls are collected during the same period as the patients samples. Patients and Methods 8
  • 9. Treatment and Evaluation: Patients with treated with cisplatin (75 mg/m2) and docetexal (75 mg/m2) on day 1 every 3 weeks. Patients were restaged for objective response after the first three cycles of chemotherapy. Patients progressing before or at first evaluation were shifted to a second-line treatment. Samples: PB taken from individuals at baseline. Centrifuged and plasma aliquots were taken for further study. Patients and Methods 9
  • 10. EGFR Quantification: Plasma EGFR concentration was determined at baseline using microtiter sandwich ELISA . Patients and Methods 10
  • 11. Statistical Analysis Comparisons and correlations with categorical variables were conducted using the Student’s t-test. The association between categorical variables was evaluated using the χ2 test. Performance of EGFR in the prediction of disease versus control status was evaluated using the receiver operating characteristic (ROC) curve. The univariate analysis (performed in parallel by KM and Cox methods) were performed along with multivariate Cox analysis. 11
  • 12. 12 ROC Curve and AUC ROC curve is a plot of sensitivity versus 1- specificity Sensitivities and specificities of a test depend on the cut-off levels that are used to define the positive and negative test results. Area under the ROC curve (AUC) provides a measure of the overall performance of a diagnostic test. The closer AUC is to 1, the better the overall diagnostic performance of the test, and a test with an AUC value is 1 then, the test is perfectly accurate.
  • 13. 13
  • 14. Results 14 Plasma sEGFR concentration in Patients and Controls Plasma sEGFR concentration found b/w both groups were statistically different (mean±2 SEM: 30.98 ng/mL ± 0.82 vs 34.91ng/mL ±1.10, P< .0001). To evaluate the potential screening utility of sEGFR concentration, ROC curves are generated to compare healthy controls to patients, thus yielding an AUC of 0.341 (95% confidence interval [CI], 0.286- 0.397). The best cut-off value for sEGFR to distinguish patients from controls was 31.62 ng/mL, resulting in 80% sensitivity and 49% specificity. This represents an acceptable specificity but a poor sensitivity, indicating that baseline sEGFR is not a strong biomarker to discriminate NSCLC patients from healthy controls.
  • 15. 15 Correlation with sEGFR conc. with clinical- pathological Variables No correlations were observed between baseline sEGFR concentration and gender, stage, PS, number of metastatic sites or locations of metastatic sites. On evaluating the correlation b/w sEGFR and treatment response, the patients with progressive disease (PD) had lower sEGFR compared with the others (CR, PR, and SD), 30.23 ng/mL ± 1.38 vs 31.72 ng/mL ± 1.11, respectively. A trend of higher sEGFR concentration in patients with ADC compared with SCC was observed, but the differences were not significant (mean ± 2 SEM; 31.74 ng/mL ± 1.14 versus 30.19 ng/mL ± 1.44, respectively, P = .081). Results
  • 16. 16 Correlation with sEGFR conc. with Survival Patients with baseline sEGFR below the cut-off value (cut-off concentration of 34.56 ng/mL) displayed no significant difference in TTP compared with patients with sEGFR above this value. Patients with baseline sEGFR ≤34.56 ng/mL had a shorter OS compared with other patients; median survival: 9.1 months (95% CI, 7.6-10.6) versus 12.2 months (95% CI, 10.4-13.9); (P= .019). The subgroup of patients with sEGFR ≤ 34.56 ng/mL had a worse prognosis but was not significantly different from the other groups in the frequencies of histologic types, PS, gender, or treatment response except differences for stage (borderline, P= .071) and age (P= .003) between subgroups. In the univariate analysis, only gender, PS, localization of metastasis (local versus distant), number of metastatic sites, as well as sEGFR were significantly associated with survival. Results
  • 17. 17
  • 18. 18
  • 19. 19
  • 20. 20
  • 21. 21
  • 22. 22
  • 23. Discussion A significantly lower concentration of sEGFR in NSCLC patients than in controls has been observed, although sEGFR is a sensitive (80% sensitivity) but not specific (49% specificity) biomarker to distinguish NSCLC patients from controls. No correlations were observed between sEGFR concentration and other well-established pathological features of advanced NSCLC. Only the patients with PD tended to have lower sEGFR concentrations, but this difference was not significant. In metastatic breast cancer, several reports show that patients with decreased concentrations of sEGFR have reduced survival whereas no studies have yet assessed the utility of plasma sEGFR as a prognosticator of NSCLC. 23
  • 24. 24
  • 25. Conclusion sEGFR is a useful prognostic biomarker in NSCLC patients. Lower sEGFR concentration was related to a poorer prognosis. Evaluation of this marker is needed in a prospective large-scale studies as a predictor of response to chemotherapy-based treatments, anti- angiogenic agents and TKIs. The poorer prognoses observed may have multiple hypothetical explanations: (1) sEGFR in the blood binds the ligand quicker than EGFR. (2) the low concentration of sEGFR may prevent the formation of sEGFR/ EGFR dimers which are capable of inhibiting the kinase activity by acting as negative regulators of the EGFR signalling cascade 25
  • 26. 26