Evolution in thoracic oncology genomics and treatment for early stage nsclc
This presentation is the property of its rightful owner.
Sponsored Links
1 / 31

Evolution in Thoracic Oncology: Genomics and Treatment for Early Stage NSCLC PowerPoint PPT Presentation


  • 50 Views
  • Uploaded on
  • Presentation posted in: General

Evolution in Thoracic Oncology: Genomics and Treatment for Early Stage NSCLC. David H. Harpole, Jr., M.D. Professor of Surgery Associate Professor of Pathology Vice-chairman, Faculty Affairs Duke University Medical Center. Who to Treat: LACE Meta-analysis: Chemotherapy Effect.

Download Presentation

Evolution in Thoracic Oncology: Genomics and Treatment for Early Stage NSCLC

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Evolution in Thoracic Oncology: Genomics and Treatment for Early Stage NSCLC

David H. Harpole, Jr., M.D.

Professor of Surgery

Associate Professor of Pathology

Vice-chairman, Faculty Affairs

Duke University Medical Center


Who to treat lace meta analysis chemotherapy effect

Who to Treat: LACEMeta-analysis: Chemotherapy Effect

Recommended for stage II-IIIA

Not recommended for stage I (A or B)


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Multivariate Risk ratio p Value

Vascular invasion 2.36 0.001

T2 tumor size 1.88 0.002

Visceral pleural + 1.75 0.022

> 15 mitoses / HPF 1.51 0.074

Risk Model in Stage I NSCLC: Histopathology

(n=410)

1.0

0.75

Survival

0.50

Size (cm) (n)5-Year Surv

0 to 215974%

2 to 420760%

> 4 4245%

0.25

p=.0002

0.0

12 24 36 48 60 72 Months

Who to treat: Tumor Biology

Harpole et al., Cancer 1995


Protein expression ihc stage 1 n 408

Protein Expression (IHC) Stage 1 (n=408)

Multivariate Survival AnalysisRisk ratiop Value

p531.630.0037

Angiogenesis factor VIII 1.4700.0333

Her2-neu1.4290.0440

CD-441.3990.0500

Rb0.7470.0738

1.0

0.75

Survival

p=0.0001

0.50

Total Markers(n)5-yr.Median

0 to 114077%Not reached

212462%Not reached

3 to 514449%58 months

0.25

12 24 36 48 60 72 Months

Who to treat: Tumor Biology

D’Amico et al. J Thor & Cardiovasc Surg, 1999


Who to treat early stage nsclc patients

Who to treat: Early Stage NSCLC Patients

Current Tools for Prognosis

  • Clinical and histopathologic factors

  • Single molecular biomarkers

But, the challenge is to provide an individualized

patient prognosis

Gene expression profiles


Current therapy for clinical stage i nsclc

Current Therapy for Clinical Stage I NSCLC

Clinical Stage 1 (45,000 patients in U.S.)

Resection

Stage I Stage II and IIIA

Identify Patients at

Higher Risk

Adjuvant Chemotherapy

(> 30% relapse)

Observation

(40% relapse)


Current therapy for clinical stage i nsclc1

Current Therapy for Clinical Stage I NSCLC

Clinical Stage 1 (45,000 patients in U.S.)

Resection

Stage I Stage II and IIIA

Observation

(40% relapse)

Adjuvant Chemotherapy

(> 30% relapse)

Develop gene expression profiles that refine risk prediction


What is a genomic signature

What is a ‘Genomic Signature’

Phenotype A (Ph A)

Phenotype B (Ph B)

Microarray analysis

Ph APh B

Probability of Ph A

‘Signature’


A signature of lung cancer recurrence

A Signature of Lung Cancer Recurrence

Low Risk

> 5yr DFS

High Risk

< 2yr DFS

Measure gene expression in tumors

Low Risk High Risk

“Metagene”

NEJM 2006


Metagene tree analysis first 5 of 100 steps

Metagene Tree Analysis: First 5 of 100 Steps

Dead

Alive

Model has 2100 Genes


Early stage nsclc genomic predictor of recurrence

Early Stage NSCLCGenomic Predictor of Recurrence

Stage I Lung Cancer

Predicted Low Risk

StageI

CALGB 30506

Predicted High Risk

NEJM 2006


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Prediction Models by Pathologic Stage

Clinical-Pathology

Prediction Model

Lung Metagene Predictor

2100 Genes

Accuracy > 90%, Sensitivity > 90%

For all stages


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Lung Metagene Predictor by Histology


Minnesota calgb 9761 validation set n 85

Minnesota + CALGB 9761 Validation Set (n=85)

Accuracy > 90%, Sensitivity > 90%

Median F/U 59 mo.


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Additional Metagene Validation Studies

  • ACOSOG Z0030; n=25 Stage 1

  • Mayo Clinic; Stage 1; n=15 Stage 1

  • Washington University; n=71 Stage 1

All together, a total of 4 independent sample sets

comprising 195 samples have been used for validation


Evolution in thoracic oncology genomics and treatment for early stage nsclc

NCI Director’s Challenge Blinded Dataset

1.0

.75

N=143 (73 Stage1A and 70 Stage 1B)

Deaths=47

Black (high risk) 31

Red (low risk) 16

Censored=96

p=0.003

Survival

.25

Overall Survival censored at 5 Years

0.0

12 24 36 48 60 72

Months


Calgb 30506 trial objectives

CALGB 30506: Trial Objectives

  • Hypothesis: A genomics prediction model (LUNG METAGENE SCORE; LMS) provides a method for selecting stage I non-small cell lung cancer (NSCLC) patients for adjuvant chemotherapy

  • Primary Objectives

    • To demonstrate a survival advantage for patients randomized to adjuvant chemotherapy compared to an observation arm (present standard of care).

      • Observe a more significant survival advantage for High-score patients treated with chemotherapy

    • To prospectively validate a prognostic indicator of survival in stage I NSCLC patients identified with LMS who are observed after resection.


Calgb 30506 trial objectives1

CALGB 30506: Trial Objectives

  • Secondary Objectives

    • Evaluate all other existing gene-based prognostic models

    • Compare the LMS with best clinico-pathologic model for survival

    • Validate of gene expression signatures from archived paraffin-embedded tumor samples

    • Quality of Life / Economics:

      • To assess QOL/Cost in all stage I patients before and periodically after resection for NSCLC.

      • To examine the impact of chemotherapy on QOL/Cost for patients in the chemotherapy arm, as compared to patients in the observation arm(s)


Calgb 30506 inclusion criteria

CALGB 30506: Inclusion Criteria

  • Pre-resection

    • Clinical T2N0 NSCLC

    • Suspicious tumor on CT size: 2.0 to 6.0 cm

      • (6 cm by CT translates to < 5.0 cm by path)

    • Mediastinal node assessment if

      • CT > 1cm

      • PET suspicious

    • Pre-registration after Informed Consent

    • No other cancer or chemotherapy in 3 years

  • At Operation

    • Verified NSCLC (if no Pre-op Dx)

    • Resectable by lobectomy (VATS or Open)

    • No clinically evidence of N2 or N1 +

      • Send frozen sections on nodes prior to enroll

    • Fresh-frozen Tumor to Duke

      • Using simple 5mm Dermal punch biopsy


Evolution in thoracic oncology genomics and treatment for early stage nsclc

After the specimen has been released by the pathologist, cut an approximate 1.0 x 1.0 x 0.5 cm block of firm grossly homogeneous lung tumor using a sterile scalpel blade.


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Using a 5mm dermal punch biopsy, cut three (3) core biopsies of equal size from the tumor.


Evolution in thoracic oncology genomics and treatment for early stage nsclc

The core biopsy may be difficult to extract from the dermal punch. If so, it can be pushed out using a wooden applicator stick inserted into the back end of the punch.


Evolution in thoracic oncology genomics and treatment for early stage nsclc

Using the forceps, immediately place one tumor biopsy sample per Cryomold onto the frozen layer of OCT.

123456-B

123456-C

123456-A


Evolution in thoracic oncology genomics and treatment for early stage nsclc

With the cryomold still on the cold plate, place a top layer of OCT onto the tumor specimen.

* The sample should be acquired / frozen within 30 minutes.*

123456-B

123456-A

123456-C


Calgb 30506 sample information flow

CALGB 30506: Sample/Information Flow

TISSUE

CALGB Site

Harpole Lab

PT CAN

REGISTER

RANDOMIZED

REGISTERED

TISSUE

Genome Trials Support Facility

MAW-3

TISSUE

3 days

Rejected

H&E

RNA

Rejected

RNA Quality

RNA

Rejected

EA: Arrays

10-14

business days

DATA

LMS SCORE

IGSP

CALGB


Calgb 30506 inclusion criteria con t

CALGB 30506: Inclusion Criteria: Con’t.

  • After Operation

    • Pathologic T1N0 and T2N0 (5% dropout)

      • N2 and N1 negative

      • Tumor >1.70 cm (up to 6.0 cm)

      • Visceral pleural invasion included

    • Inadequate tumor sample (10% Dropout)

      • > 50% necrosis

      • < 12 µg quality RNA

      • Good quality Array data generated

  • Formal Registration


Calgb 30506 statistical assumptions

CALGB 30506: Statistical Assumptions

  • Observation arm Survival for 1.7 to 6.0 cm stage I

    60% at 5-years

    • Low-score observation survival = 70+%

      • (10+% increase)

    • High-score observation survival = <50%

      • (10+% decrease)

  • Chemotherapy Treatment arm survival

    68-70%*(10-15% increase = HR 1.3 to 1.5)

  • High-score chemotherapy advantage

    • (15+% increase = HR 1.67-2.0)

      *Based on ANITA and NCI-C JBR-10

      30506 is powered based on the chemotherapy

      treatment study: 85% with a two-sided p<0.05.

      Patients and treating physicians are Blinded to LMS


Calgb 30506 schema stage ia ib

CALGB 30506Schema (Stage IA/IB)

Resection T (1.70 to 6.0) N0 Patients + Array

LM Score <0.55; 60% LM Score > 0.55; 40%

Randomize

Randomize

Adjuvant Chemotherapy

Adjuvant Chemotherapy

Observation

Observation

LM Scores Blinded to Investigators, n=1525

(1296 after 15% Ineligibility)


Calgb 30506 treatment plan

CALGB 30506: Treatment Plan

  • Assignment to Treatment Arm by Stats

    • Observation or Treatment

  • Chemotherapy within 12 weeks of resection

    • Platinum Doublets to mirror ECOG 1505

      • Cisplatin + Docetaxel

      • Cisplatin + Gemcitabine

      • Cisplatin + Vinorelbine

      • Cisplatin + Pemetrexed - added soon

        This will allow combining these data with the

        ECOG 1505 chemotherapy-alone arm


Conclusions

Conclusions

1.CALGB 30506 is NCI-CTEP approved and activated in the CTSU. It has been endorsed by ACOSOG, ECOG, RTOG and Canadian sites. The tissue acquisition, processing, Affymetrix Genechip array generation and data analysis are funded by an NCI RO1.

2.It is hopeful that the use of this genomic prediction model will aid in the appropriate selection of stage 1 patients who will benefit from adjuvant chemotherapy.


Enrollment tips

Enrollment Tips

  • It is known that node + patients have up to 15% increased survival with adjuvant chemotherapy

  • It might be the case for node-negative tumors, but we need a trial to show that (standard is no chemo)

  • Everyone gets an equal chance of observation or chemotherapy

  • Everyone is does not know the score of your tumor except the NCI statisticians

  • You can pick the pair of drugs with your medical oncologist These are FDA-approved Standard Doses of Standard Drugs for adjuvant therapy in NSCLC. No experimental use. These are covered by insurance and mandated coverage by Medicare/Medicaid.


  • Login