Daya Upadhyay, MDAssociate Professor of Clinical Medicine, UCSF

Medical Director, Lung Nodule ProgramDirector, Translational Research in MedicinePulmonary, Critical Care & Sleep Medicine

University of California San Francisco, Fresno

UCSF

University of CaliforniaSan Francisco

School of MedicineFresno Medical Education Program

How Can We Improve

Lung Cancer Survival UCSFCRMCCCC

Future Directions

1. How to Beat the Survival Time Clock

Stage 5-Yr Survival

I A 75%I B 55%II A 50%II B 40%III A 10-35%III B 5%IV 2%

2. Decoding The Cancer Gene

5-Year Survival in Lung Cancer is 17%

Lung Cancer Kills More People Than Breast Cancer, Colon Cancer and Prostate Cancer Combined

These data have not changed in the past 15 years

Lung

Can

cer

ColonBreast

Prostate

158,040 

SEER Cancer Statistics Review, NCI.

Lung Cancer is the Leading Cause of Cancer Deaths

SEER Cancer Statistics Review, NCI,

Lung Cancer for 2014

NCI, Cancer Statistics

Prevalence and mortality continue to remain high in Lung Cancer 215,000 are newly diagnosed and 158,000 die of lung cancer

each year

Smoking and Gender Variability In Prevalence of Lung Cancer

From 1974-1994: Prevalence of Lung Cancer in women Increased by 150%;

Death Rates Increased by 600%.

Cigarette Ad 1968 Target women to smokeYou've come a long way, baby

Women

Men

Lung Cancer Prevalence

Tobacco Control Cancer in Men and in cancer in Women

Women are 1.5 times more likely to develop lung cancer than men with same amount of smoking

Early Stage Lung Cancer is Asymptomatic. Therefore Diagnosis is delayed When symptoms occur, its too late

Why is Survival Poor in Lung Cancer

Continued Smoking increases the Risk for Cancer Continued Smoking Decreases response to Therapy “EARLY DIAGNOSIS” improves Lung Cancer survival; however, Early Diagnosis is difficult.

Why is Survival Poor in Lung Cancer

Nicotine Enhances Tumor

Angiogenesis,Tumor Growth

Despite multimillion dollar research on therapy, survival in lung cancer is 17%

“EARLY DIAGNOSIS” is the ONLY factor that improves survival in Lung Cancer. However, the progress is slow.

Why is Survival Poor in Lung CancerSEER Cancer Statistics, NCI

NCI, Office Budget Portfolio

Breast Prostate Colon Lung0

30000

60000

90000

120000

150000

180000 Death RateResearch Funding

Goals

Improving Lung Cancer

Survival

Prevention Early Diagnosis

Early Treatment

Prevention

Lung Cancer is a Preventable Disease

Federal Tax

Nearly 85% Of Cancer Occur Secondary To Smoking

Smoking Cessation Reduces Lung Cancer Risk

Smoking CessationRisk

Prevention: Smoking Cessation: Start Early

90% of Smokers Begin Before Age 1810% of high school kids & 3% of middle school kids smoke Educate Adults and Kids about bad effects of smokingEvery day over 700 kids become regular daily smokers.

We Run a Anti-Smoking Education Program for Schools

Other Smoke

Cigars, Smokeless Tobacco, Chew Tobacco: Are equally harmful

Electronic Cigarettes: Contain Nicotine, which is a carcinogen & Addicting substance

Studies show that E-Cigarettes DO NOT help in Quitting

Electronic Cigarettes Change Gene Expression In Lung Epithelium Similar to Tobacco Smoke

S. J. Park et al. Clin. Cancer Res. 20, B16; 2014).

Nature 508:159;2014

Do Electronic Cigarettes Cause Cancer?

E-Cigarettes First moved into American market in 2007

Became popular in 2010

Target Year2027

-2030

Smoking Cessation Program

Dedicated Smoking Cessation Program At CRMC – UCSF Fresno

We Run a Anti-Smoking Education Program for Schools American College of Chest Physicians

Combination of Risk Factor

Lung Cancer in Non-Smokers

Accounts to <10% CancerWomen > Men Asian > non-AsianEGFR Mutations seenAny Age

Goals

Improving Lung Cancer

Survival

Prevention Early Diagnosis

Early Treatment

Early Diagnosis

CT Screening may be the First Step In Early Diagnosis

Identify High Risk Population

2011 National Lung Cancer Screening Trial

SEER Cancer Statistics, NCI.

Target Population at risk1. Smoker who are at high risk2. Target Age Group: 50-79yrs

Stage / Survival%IA:75% IIIA: 10% 65%IA:75% IB: 55% 20%IIB:40% IIIB: 5% 35%

Stage / Survival %

Why should we Speed up the Diagnosis?

Survival Time Clock

Stage TNM Rx 5-Yr Survival

I A T1N0M0 Surgical Resection

orSBRT

+/- Chemoprevention

75%I B T2N0M0 55%II A T1N1M0 50%

II B T2N1M0T3N0M0 40%

III A T1-3N2M0T3N1M0

Surgery + Chemo-XRT 10-35%

III B T1-4N3M0 Chemo-XRT 5%IV Any M1 Chemo 2% Our Goal

Symptoms / SyndromesSymptoms due to Metastases

NO SYMPTOMS

Fatigue, Cough, Dyspnea, Anorexia, Weight lossHemoptysis Chest pain Recurrent infections

Do not offer a Chest X-ray as an option for Lung Cancer Screening

Chest Radiographs are not very useful

75y man smoker incidentalSk

72y man >30 pack year smoking, admitted for CHFGI

66y woman active heavy smoker

DMC31y old woman non-smoker, asymptomatic

Three subtypes: mucinous, non-mucinous, and a mixed mucinous and non-mucinous or indeterminate form.

AdenocarcinomaBronchioloalveolar Carcinoma (BAC)

Radiology (2013) 266(1):304-17.Semisolid Lung Nodule

Most Critical Question is –

It’s Abnormal, What do I do Now?????

Any MD can identify High Risk Patients and can order Chest CTs

Diagnosis is particularly challenging in Endemic Cocci Area

Lung Nodule ProgramUCSFCRMCCCC

Multi-disciplinary Team Approach

Imaging, CT scanTissue Diagnosis- Cytology, Histology

Molecular marker –Mutational studiesIR or CT guided Fine-Needle AspirationBronchoscopic Biopsies Transbronchial Needle Aspiration (TBNA) Endobronchial Ultrasound Biopsy (EBUS) Electro-magnetic Navigation guided Biopsy Esophageal Ultrasound Needle Aspiration Trans-thoracic Needle Aspiration (TTNA)Mediastinoscopy, VATS, Surgical Biopsy

SNapShot Mutation Analysis: EGFR, ALK etc Brain MRIPFTBone Scan

Diagnostic Interventions

Histology of Lung Cancer

NSCLC SCL

Histology: Adenocarcinoma: 50% , Squamous: 20%, Large cell: 3%, Small Cell: 25%, Other: 2%

Non-small Cell Lung Cancer (NSCLC): 75% of Lung Cancers

Early Diagnosis & Early Surgery Offer Best Survival in Lung Cancer

ELC

AP,

NEJ

M 2

006;

355:

1763

-71

Barriers to Surgical Resection of Lung Cancer

Staging in PracticePhysiological Anatomic

Barriers to Surgical Resection

Multi-disciplinary Team Conference

Goals

Improving Lung Cancer

Survival

Prevention Early Diagnosis

Early TreatmentEarly Treatment

Early Treatment

Minimally Invasive Surgery

ChemotherapyInfusion Center

Early Diagnosis of Lung Cancer

Stage / Survival%IA:75% IIIA:10% 65%IA:75% IB: 55% 20%IIB:40% IIIB:5% 35%

Stage / Survival %

Why should we Speed up the Diagnosis? Survival Time Clock

Survival in women is slightly better than men

Early Diagnosis & Early Surgery Offer Best Survival in Lung Cancer

ELC

AP,

NEJ

M 2

006;

355:

1763

-71

Che

st. 2

013;

144(

4):1

238-

1244

.

Early Stage & Early Surgery show Better Outcome in Lung Cancer

Stereotactic Body Radiation Therapy (SBRT)

Surgery vs SBRT

Radiotherapy & Oncology, 2011;101(2):240-244

Stereotactic Radiotherapy Versus Surgery In Stage I NSCLC

Stage I NSCLC Surgery Vs SBRT

No Difference In Survival

Outcomes of Stereotactic Body Radiotherapy In Potentially Operable Stage I NSCLS

Int J Radiat Oncol Biol Phys. 2012;83(1):348-53.

Disease control 98%:1y ; 93%:3y Median survival in potentially operable NSCLC Rxed with SBRT was >5 years.

Personalized Treatment Approach

Has been shown to be very effective

The Digital Future of Molecular Medicine

It is based on decoding of the human gene Use molecular biology technology to

advanced therapy in cancer and diabetes. Diseases are not homogenous

Drugs, Surgery, Radiation, Vaccines, HormonesAdd Targeted Personalized Rx Approach

PD1PDL1

Molecular Targets for Therapy(FDA-approved therapies & Clinical Trials)

NewerPD-1 PD-L1

Personalized Treatment Approach

Use of Tumor Tissue and Blood to detect Cancer Mutation

SNaPshot analysis

EGFR, KRAS, PIK3, ALK, ROS1, PDL1, PD1 CytoGenetic Analysis By qPCR, Allelespecific qPCR, Sequencing

Mutation Targeted Treatment

EGFR

Personalized Treatment ApproachEGFR Targeted Therapy

Lancet Oncol. 2011 Aug;12(8):735-42.

Personalized Treatment ApproachALK Targeted Therapy

N Engl J Med 2013; 368:2385-2394

Personalized Treatment ApproachPD1 and PDL1 Targeted Therapy

Molecular Targets for Therapy(FDA-approved therapies for solid tumors)

Extracellular targetsEGFR/HER (cetuximab, panitumumab, trastuzumab)VEGF (bevacizumab)HER2 (trastuzumab)Intracellular targetsEGFR (erlotinib)VEGFR (sorafenib, sunitinib)mTOR (temsirolimus)PDGFR (sorafenib, sunitinib)RAF/MAP kinase (sorafenib)HER2/EGFR1 (lapatinib)C-kit (sunitinib)

EGFR and KRAS mutations in NSCLC are mutually exclusive

NSCLC patients with EGFR mutations respond well to EGFR-Tyrosin Kinase Inhibitors (EGFR-TKIs)

NSCLC patients with KRAS mutations may be less likely to respond to EGFR-TKIs

EML4-ALK NSCLC: A unique subset of NSCLC who respond effectively to ALK inhibitors

Immunotherapy for Lung CancerTherapeutic Vaccines for Lung Cancer

Monoclonal Antibodies Bavituximab,  (SUNRISE; NCT01999673). Rilotumumab, (NCT02154490)

Immune Checkpoint Inhibitors: CTLA-4 antibodies Ipilimumab (Yervoy™), targets the CTLA-4 a  Tremelimumab (NCT01655888 and NCT01649024)

PD-1 antibodies Nivolumab (BMS-936558) (NCT01673867) MK-3475 phase III (NCT01905657).

PD-L1 antibodies MPDL3280A (NCT01846416) MEDI4736 (NCT01693562), (NCT02154490)

http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/lung-cancer#sthash.d5N3xlk8.dpuf

Therapeutic Vaccines: MAGE-3 and NY-ESO-1 Antigen-based immunotherapies Belagenpumatucel-L (NCT00676507) Tergenpumatucel-L (NCT01774578). GV1001 targets hTERT (telomerase ) TG4010 (NCT01383148) INGN, vaccine targets p53 (NCT01383148) A vaccine targeting the WT1 (NCT01265433) CV9202 RNActive®-derived cancer vaccine

Adoptive T Cell Transfer

Genetically Engineered T cells – target CEA (in 30% of NSCLC).Genetically Engineered T cells – target  NY-ESO-1 (NCT00670748)

Poor Prognostic Factors

Presence of pulmonary symptoms Large tumor size (>3 cm) Non-squamous histology Poorly Differentiated Metastases to multiple lymph nodes within a

TNM-defined nodal stations Vascular invasion.

The Digital Future of Molecular MedicineIs a Bright Ray of Hope

Our goal is to examine mutations by molecular studies in all patients to direct personalized treatment.

Very Expensive Mutation Genetic Tests, Not frequently Covered by Insurances

Limitations

Early Diagnosis improves survival in Lung CancerCT Screening can saves lives in very selected patients It is expensive; Health care cost is very high Smoking cessation is important in reducing cancer riskPET Scan are False Positive in our Cocci areaAccess to Organized Multidisciplinary Lung Nodule

Program is essential for early diagnosis & managementMolecular marker Targeted Therapy is the futurePrevention, Early Diagnosis and Early Treatment can

help improve survival in lung cancer.

Summary and Conclusion

Thank You