Achieving Precision Medicine for Lung Cancer in Asians

Precision Medicine: Targeted therapies elicit high response rates in molecularly defined cancers

Bcr-Abl

ChronicMyeloid Leukemia

EGFR*

EGFR-mutatedNon-Small Cell Lung Cancer

ImatinibErlotinib/GefitinibSpecific to Asia

EGFR mutation more frequent in Southeast Asian populations

BIM deletion polymorphism confers resistance, and found in Asians

Lung Cancer

Asians have higher non-smoking lung cancer than Westerns

Why do Asians have higher non-smoking lung cancer than Westerns?

Is it due to second-hand smoke?

• Are smokers and never-smokers tumor profiles similar?

• If yes, then second-hand smoke is cause of higher incidence.

• Different from Western countries?

• Something unique to Asian causing differences?

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• Sequenced 30 genomes of lung cancer patients

Whole-genome sequencing of asian lung cancers: second-hand smoke unlikely to be responsible for higher incidence of lung cancer among Asian never-smokers.Cancer Research 2014 Nov 1;74(21):6071-81.

Distinct mutation signatures between smokers and non-smokers

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Asian non-smokers look like European non-smokers (high G.C > A.T)Asian smokers look like European smokers (high G.C > T.A)

High incidence of lung cancer in Asian non-smokers is unlikely due to second-hand smoke

All the never-smokers

Contains only smokers

G.C > A.T observed before for nonsmokers

G.C > T.A. seen before for smokers

Distinct mutation signatures between smokers and non-smokers

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Asian non-smokers look like European non-smokers (high G.C > A.T)Asian smokers look like European smokers (high G.C > T.A)

High incidence of lung cancer in Asian non-smokers is unlikely due to second-hand smoke

All the never-smokers

Contains only smokers

~1/2 of ex-smokers/smokers classified with never-smokers

Evidence #1: Some smokers have a nonsmoker molecular signature

Evidence #2: Some smokers have a nonsmoker molecular signature

Evidence #3: Some smokers have a nonsmoker molecular signature

• Half of the smokers/ex-smokers have a nonsmoker molecular signature

• Smoking status insufficient

Mutations (such as EGFR) drive cancer regardless of smoking status

Smokers with non-smoker signature

EGFRDoes not have EGFR

Lung Cancer Treatment

chemotherapy

LungCancer

SequenceEGFR

EGFR mutant

EGFR wildtype

gefitinib

chemotherapy

First line of questioning is phenotype, then later genotype

Phenotype << Genotype

Conclusion

• Smokers can have a non-smoking molecular signature

• Sequence for EGFR mutation, regardless of smoking status

• Molecular signature confirms what’s already in practice in Singapore and Japan