Personalized Therapy of Lung Cancer

2011 Winter Lung Cancer Conference

Thomas J. Lynch, Jr., M.D.Jonathan and Richard Sackler Professor of Internal Medicine

Director, Yale Cancer CenterPhysician-in-Chief, Smilow Cancer Hospital

Lung Cancer 2011

• USA– 190,000 cases of lung cancer– 165,000 deaths– 165,300 cases of NSCLC– 115,000 cases of adenocarcinoma– 28,500 cases of lung cancer in never smokers

• Global– 1.4 million deaths from lung cancer

NCI SEER Cancer Statistics, WHO Fact Sheet.

Cancer 2011• Cancer is a disease caused by abnormal

genes that “drive” either excessive cell growth or inadequate cell destruction

• Imbalance of growth and death signals leads to growth of cancer cells into tumors

• Tumors then proceed to grow and metastasize

• Understanding which genes drive which cancers will provide a “roadmap” to curing cancer

Major Classes of Genomic Alterations that Give Rise to Cancer

• Point mutations• Copy number alterations

Deletions Amplifications

• Translocations Examples: BCR-ABL, EML4, ALK

MacConall LE and Garraway LA. J Clin Oncol 2010;28:5219-28.

Kate’s Story

• March 2002: Shortness of breath• April 2002: Lung cancer in brain, lung and

lymph nodes• Summer 2002: Chemotherapy• November 2002: Progression in liver

Kate November 2002 Pre Rx

Kate April 2003

Giaccone G et al. J Clin Oncol 2004;22:777-84. Herbst RS et al. J Clin Oncol 2004;22:785-94.

INTACT Trials: 1-Year Overall Survival

INTACT 1

• Gefitinib 500 mg + gemcitabine/cisplatin, 9.9 months

• Gefitinib 250 mg + gemcitabine/cisplatin, 9.9 months

• Placebo, 11.1 months

INTACT 2

• Gefitinib 500 mg + paclitaxel/carboplatin, 8.7 months

• Gefitinib 250 mg + paclitaxel/carboplatin, 9.8 months

• Placebo, 9.9 months

Sequist LV et al. J Clin Oncol 2008;26(15):2442-9.

First-Line Gefitinib in Patients with Advanced NSCLC Harboring

Somatic EGFR Mutations

• Mutations detected in 34/98 patients who underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21

– In-frame deletions of 11-15 bp, 53%

– L858R, 26%

– Atypical, 21%

• Objective response rate, 55%

• Median progression-free survival, 9.2 months

Resistance

There are 2 robustly described TKI-resistance mechanisms: T790M in EGFR and MET amplification

1 patient with both T790M and L858R had a best response of SD and remained on treatment for 55 days

Source: Sequist LV et al. Proc ASCO 2007. Abstract 7504

T790M

• Gatekeeper mutation present in nearly 60% of acquired resistance

• Rare familial germline mutations found• Detected at diagnosis in CTCs and circulating

DNA in 30% of patients using highly sensitive methods

• Efforts to target T790M are emerging

T790M

• Irreversible Dual (EGFR, Her-2) kinases have not yet proven effective in this setting

• Novel T790M specific inhibitor (Nathanael Gray-DFCI) under development

• Combination therapy might hold best hope

Adeno

Squam

Large

Small

KRAS

Unknown

EGFRHER2

BRAFALK fusion

PIK3CAMEK1

ROS fusionPDGFR amp

2011: Lung Adenoca-Multiple Molecular Subsets

Courtesy William Pao

Adeno

Squam

Large

Small

KRAS

Unknown

EGFR

HER2

ALK fusion

2011: Never Smoker Lung Adenoca (US)-Almost All Molecular Subsets Defined!

Pham D et al. J Clin Oncol 2006;24(11):1700.Stephens P et al. Nature 2004;431(7008):525.Shaw AT et al. J Clin Oncol 2009;27(26):4247.Riely GJ et al. Clin Cancer Res 2008;14(18):5731.

Somatic Mutations Affect Key Pathways in Lung Adenocarcinoma

• Discovery of more than 1,000 somatic mutations after sequencing 623 genes with known or potential relationships to cancer

• Identified 26/623 genes that are mutated at a significantly high frequency

– Most frequent: TP53, KRAS, STK11, EGFR

– Less frequent: LRP1B, KDR, RB1, LTK, SLC38A3, NRAS

• Genetic alterations frequently occur in genes of the MAPK, p53, Wnt and mTOR pathways

Ding L et al. Nature 2008;455:1069-75.

McDermott U et al. N Engl J Med 2011;364:340-50.

Tumor Tissue Heterogeneity and MicrodissectionTumor Tissue Heterogeneity and Microdissection

A.A. H&E micrographH&E micrographof prostate carcinoma of prostate carcinoma showing epithelial tissue showing epithelial tissue (red arrows) and stroma(red arrows) and stroma(black arrow).(black arrow).

B.B. Area of epithelial Area of epithelial tissue to be dissected out-tissue to be dissected out-lined by etching with lined by etching with laser.laser.

C.C. Tissue section afterTissue section afterremoval of outlined tissue.removal of outlined tissue.

D. Removed tissue.D. Removed tissue.

EGFREGFR mutation assay on normal mutation assay on normal tonsil DNAtonsil DNA

EGFREGFR mutation assay on DNA of a mutation assay on DNA of a formalin-fixed, paraffin-embedded formalin-fixed, paraffin-embedded sample of lung tumor with a sample of lung tumor with a heterozygous mutationheterozygous mutation

EGFR G719A, G719S, G719CE746_A750del, E746_S752>VL747_T751, L747_P753>ST790ML858RL861Q

KRAS G12S, G12R, G12D, G12V,G12C, G12AG13C, G13S, G13R, G13DQ61K, Q61L, Q61R, Q61H

BRAF V600E, V600K

NRAS G12C, G12S, G12R, G12D,G12V, G12AG13R, G13C, G13V, G13D,G13AQ61K, Q61L, Q61R, Q61H,Q61P

PIK3CA R88QE542KE545K, E545A, E545GQ546K, Q546RH1047Y, H1047L, H1047RG1049S, G1049R

PTEN R130*R173CR233*K267fs*

11

14

17

4

12

2

Gene Mutations tested Cancer type Targeted therapy

Total = 60 mutations

Lung (26%) TKIs: erlotinib, gefitinib (adenocarcinoma)

Lung (17%), colon (15%) Erlotinib, gefitinib;pancreas, biliary tract, cetuximabendometrium, ovary

Melanoma (50%), thyroid, PLX4032,biliary tract, colon (12%) GSK2118436

Melanoma (15%), Drugs targetingleukemia, colon (3%) RAS/RAF/MEK pathway

Breast, urinary tract, Drugs targetingendometrium, colon (13%), PI3K/AKT/mTORstomach, melanoma (5%) pathway

Endometrium, brain,prostate, colon (10%),melanoma (10-30%)

Genome Statistics

• 29,000 human genes

• Average gene 3000 bases but wide variation exists

• 99.9% of our bases are exactly the same from person to person

• Functions are unknown for 50% of the discovered genes

Progress in Sequencing the Human Genome• 2000

– 12 years– 1,800,000,000 USD

• 2010– 12 days– 20,000 USD

• 2011– 5 days– 5,000 USD

Yale Genome Statistics

• Human genome 3.2 billion bases or 3.2 Gbases

• Sept 2010 Yale sequences 1.8 trillion bases or 1800 Gbases

• In September Yale sequenced the equivalent of 562 human genomes!

• In January Yale sequenced 1300 human genomes!

Post Genome World• 2008 - EGFR and Ras mutation testing

routine• 2009 - Molecular genotyping - snapshot• 2010 - Whole genome sequencing begins

experimentally• 2012 - Routine WGS available to patients

Will we be ready?