Evolution in thoracic oncology genomics and treatment for early stage nsclc
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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.

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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: LACE Early Stage NSCLCMeta-analysis: Chemotherapy Effect

Recommended for stage II-IIIA

Not recommended for stage I (A or B)


Multivariate Risk ratio p Value Early Stage NSCLC

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 2 159 74%

2 to 4 207 60%

> 4 42 45%

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) Early Stage NSCLC

Multivariate Survival Analysis Risk ratio p Value

p53 1.63 0.0037

Angiogenesis factor VIII 1.470 0.0333

Her2-neu 1.429 0.0440

CD-44 1.399 0.0500

Rb 0.747 0.0738

1.0

0.75

Survival

p=0.0001

0.50

Total Markers (n) 5-yr. Median

0 to 1 140 77% Not reached

2 124 62% Not reached

3 to 5 144 49% 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 Early Stage NSCLC

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 Early Stage 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 Early Stage 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’ Early Stage NSCLC

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 Early Stage NSCLC

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 Early Stage NSCLC

Dead

Alive

Model has 2100 Genes


Early stage nsclc genomic predictor of recurrence
Early Stage NSCLC Early Stage NSCLCGenomic Predictor of Recurrence

Stage I Lung Cancer

Predicted Low Risk

StageI

CALGB 30506

Predicted High Risk

NEJM 2006


Prediction Models by Pathologic Stage Early Stage NSCLC

Clinical-Pathology

Prediction Model

Lung Metagene Predictor

2100 Genes

Accuracy > 90%, Sensitivity > 90%

For all stages



Minnesota calgb 9761 validation set n 85
Minnesota + CALGB 9761 Validation Set (n=85) Early Stage NSCLC

Accuracy > 90%, Sensitivity > 90%

Median F/U 59 mo.


Additional Metagene Validation Studies Early Stage NSCLC

  • 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


NCI Director’s Challenge Blinded Dataset Early Stage NSCLC

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 Early Stage NSCLC

  • 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 Early Stage NSCLC

  • 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 Early Stage NSCLC

  • 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


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.



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.


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

123456-B

123456-C

123456-A


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 of OCT onto the tumor specimen.

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. of OCT onto the tumor specimen.

  • 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 of OCT onto the tumor specimen.

  • 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 30506 of OCT onto the tumor specimen.Schema (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 of OCT onto the tumor specimen.

  • 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 of OCT onto the tumor specimen.

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 of OCT onto the tumor specimen.

  • 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.


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