This document discusses Daya Upadhyay, an Associate Professor at UCSF who is the Medical Director of the Lung Nodule Program and Director of Translational Research in Medicine. It provides information on lung cancer survival rates by stage and discusses reasons for the generally poor survival in lung cancer, such as late stage at diagnosis and continued smoking. It outlines goals and strategies to improve lung cancer survival through prevention, early diagnosis, and early treatment approaches including screening, diagnostic techniques, surgery, radiation, and personalized treatment based on cancer gene mutations.

1. Daya Upadhyay, MD
Associate Professor of Clinical Medicine, UCSF
Medical Director, Lung Nodule Program
Director, Translational Research in Medicine
Pulmonary, Critical Care & Sleep Medicine
University of California San Francisco, Fresno
UCSF
UniversityofCalifornia
SanFrancisco
SchoolofMedicine
FresnoMedicalEducationProgram
How Can We
Improve
Lung Cancer Survival
UCSF
CRMC
CCC

2. 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

3. 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
LungCancer
Colon
Breast
Prostate
158,040
SEERCancer Statistics Review, NCI.

4. Lung Cancer is the Leading Cause
of Cancer Deaths
SEERCancer 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

5. 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 smoke
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

6.  Early Stage Lung Cancer is Asymptomatic.
 Therefore Diagnosis is delayed
 When symptoms occur, its too late
Why is Survival Poor in Lung Cancer

7.  Continued Smoking increases the Risk for Cancer
 Continued Smoking Decreases response to Therapy
 improves Lung Cancer survival; however,
 Early Diagnosis is difficult.
Why is Survival Poor in Lung Cancer
Nicotine
Enhances Tumor
Angiogenesis,
Tumor Growth

8. Despite multimillion dollar research on therapy, survival in lung
cancer is 17%
 is the ONLY factor that improves
survival in Lung Cancer. However, the progress is slow.
Why is Survival Poor in Lung Cancer
SEER Cancer Statistics, NCI
NCI, Office Budget Portfolio
0
30000
60000
90000
120000
150000
180000
Breast Prostate Colon Lung
Death Rate
Research
Funding

9. Goals
Improving
Lung Cancer
Survival
Prevention Early Diagnosis
Early Treatment
Prevention

10. Lung Cancer is a Preventable Disease
Federal Tax
Nearly 85% Of Cancer Occur Secondary To Smoking

11. Smoking Cessation Reduces
Lung Cancer Risk
Smoking CessationRisk

12. Prevention: Smoking Cessation: Start Early
90% of Smokers Begin Before Age 18
10% of high school kids & 3% of middle school kids smoke
Educate Adults and Kids about bad effects of smoking
Every day over 700 kids become regular daily smokers.
 We Run a Anti-Smoking Education Program for Schools

14. 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

15. Do Electronic Cigarettes Cause Cancer?
 E-Cigarettes
First moved into
American market
in 2007
 Became popular
in 2010
Target Year
2027
-
2030

16. 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

17. Combination of Risk Factor

18. Lung Cancer in Non-Smokers
Accounts to <10% Cancer
Women > Men
Asian > non-Asian
EGFR Mutations seen
Any Age

19. Goals
Improving
Lung Cancer
Survival
Prevention Early Diagnosis
Early Treatment
Early Diagnosis

20. 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 risk
1. Smoker who are at high risk
2. Target Age Group: 50-79yrs

21. 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
or
SBRT
+/- Chemo
prevention
75%
I B T2N0M0 55%
II A T1N1M0 50%
II B
T2N1M0
T3N0M0
40%
III A
T1-3N2M0
T3N1M0
Surgery +
Chemo-XRT 10-35%
III B T1-4N3M0 Chemo-XRT 5%
IV Any M1 Chemo 2%
Our Goal

22. Symptoms / Syndromes
Symptoms due to Metastases
NO SYMPTOMS
 Fatigue, Cough, Dyspnea,
 Anorexia, Weight loss
 Hemoptysis
 Chest pain
 Recurrent infections

23. Do not offer a Chest X-ray as an option for Lung
Cancer Screening
Chest Radiographs are not very useful

24. 75y man smoker incidental
Sk

25. 72y man >30 pack year smoking, admitted for CHF
GI

26. 66y woman active heavy smoker

27. DMC
31y old woman non-smoker, asymptomatic

29. Three subtypes: mucinous, non-mucinous, and a mixed
mucinous and non-mucinous or indeterminate form.
Adenocarcinoma
Bronchioloalveolar Carcinoma (BAC)

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

31. 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

32. Lung Nodule Program
UCSF
CRMC
CCC
Multi-disciplinary Team Approach

33. Imaging, CT scan
Tissue Diagnosis- Cytology, Histology
Molecular marker –Mutational studies
IR or CT guided Fine-Needle Aspiration
Bronchoscopic 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 MRI
PFT
Bone Scan
Diagnostic Interventions

34. 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

35. Early Diagnosis & Early Surgery Offer
Best Survival in Lung Cancer
ELCAP,NEJM2006;355:1763-71

36. Barriers to Surgical Resection of
Lung Cancer
Staging in Practice
Physiological Anatomic
Barriers to Surgical Resection

37. Multi-disciplinary Team Conference

38. Goals
Improving
Lung Cancer
Survival
Prevention Early Diagnosis
Early TreatmentEarly Treatment

39. Early Treatment
Minimally Invasive Surgery
Chemotherapy
Infusion Center

40. 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

41. Early Diagnosis & Early Surgery Offer
Best Survival in Lung Cancer
ELCAP,NEJM2006;355:1763-71

42. Chest.2013;144(4):1238-1244.
Early Stage & Early Surgery show
Better Outcome in Lung Cancer

43. 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.

44. Personalized Treatment Approach
Has been shown to be very effective

45. 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, Hormones
Add Targeted Personalized Rx Approach

46. PD1
PDL1
Molecular Targets for Therapy
(FDA-approved therapies & Clinical Trials)
Newer
PD-1
PD-L1

47. 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

48. Personalized Treatment Approach
EGFR Targeted Therapy
Lancet Oncol. 2011 Aug;12(8):735-42.

50. Personalized Treatment Approach
ALK Targeted Therapy
N Engl J Med 2013; 368:2385-2394

51. Personalized Treatment Approach
PD1 and PDL1 Targeted Therapy

52. Molecular Targets for Therapy
(FDA-approved therapies for solid tumors)
Extracellular targets
EGFR/HER (cetuximab,
panitumumab, trastuzumab)
VEGF (bevacizumab)
HER2 (trastuzumab)
Intracellular targets
EGFR (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

53. Immunotherapy for Lung Cancer
Therapeutic 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)

54. 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.

58. The Digital Future of Molecular Medicine
Is 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

59. Early Diagnosis improves survival in Lung Cancer
CT Screening can saves lives in very selected patients
It is expensive; Health care cost is very high
Smoking cessation is important in reducing cancer risk
PET Scan are False Positive in our Cocci area
Access to Organized Multidisciplinary Lung Nodule
Program is essential for early diagnosis & management
Molecular marker Targeted Therapy is the future
Prevention, Early Diagnosis and Early Treatment can
help improve survival in lung cancer.
Summary and Conclusion

60. Thank You