1. Adam J. Hayek, DO PGY-6 Pulmonary and Critical Care Fellow
SPN and Lung Cancer
Adam J. Hayek, DO PGY-6
Pulmonary and Critical Care Fellow

2. GOALS Lung Cancer Incidence & Mortality
Dealing with Incidental Found Nodules
You are responsible for all ED “un” necessary imaging
Lung Cancer Screening
Molecular Evolution
Molecular Evaluation
New directed therapy
Make you a believer that in the near future lung cancer will be a chronic illness just like COPD with even better survival
Acquired Resistance
Liquid Biopsy

3. Cancer Statistics 2015
American Cancer Society, Cancer Statistics; 2015

4. Survival Trend Primary Site New Cases (n) Deaths (n) 5- Year Survival
5 Year Survival Δ
Prostate
220,800
27,540
68%
99%
+31%
Breast
234,190
40,730
75%
91%
+16%
Colorectal
132,700
49,700
51%
65%
+14%
Lung
221,200
158,040
12%
18%
+6%
Pancreas
48,960
40,560 3% 7%
+4%
American Cancer Society, Cancer Statistics; 2015

5. Why?? Survival Trend Primary Site New Cases (n) Deaths (n)
5- Year Survival
5 Year Survival Δ
Prostate
220,800
27,540
68%
99%
+31%
Breast
234,190
40,730
75%
91%
+16%
Colorectal
132,700
49,700
51%
65%
+14%
Lung
221,200
158,040
12%
18%
+6%
Pancreas
48,960
40,560 3% 7%
+4%
Why??
American Cancer Society, Cancer Statistics; 2015

6. Lung Cancer at Diagnosis: 2002-2008
Lung Cancer Survival
Symptomatic Lung Cancer generally advanced stage disease and not currently curable
Lung Cancer at Diagnosis:
226,000 New Diagnosis
Localized 15%
Regional 22%
Distant 56%
Wender et al CA Cancer J Clin 2013

7. Screening Primary Site New Cases (n) Deaths (n) 5- Year Survival
5 Year Survival Δ
Prostate
220,800
27,540
68%
99%
+31%
Breast
234,190
40,730
75%
91%
+16%
Colorectal
132,700
49,700
51%
65%
+14%
Lung
221,200
158,040
12%
18%
+6%
Screening
PSA
Mammography
Colonoscopy
LDCT CMS 2/15/2015
American Cancer Society, Cancer Statistics; 2015

8. National Lung Cancer Screening Trial (NLST)
Age 55-74
Smoker
Former smoker quit < 15 yrs ago
30 pk yr
20% reduction in lung cancer
Young, et al.
Subgroup analysis of 18,714 with spirometry
34% had COPD accounting for 52% cancer cases
Young, et al. AJRCCM 2015;192:

9. SPN Found round or oval area of increased opacity
Spiculated or lobulated
Can be non solid, part solid or solid
<3 cm

10. DDx Benign: Malignant: Lung cancer Metastasis Carcinoid Lymphoma
Pneumonia
Granuloma
Hamartoma
AVM
Pulmonary artery pseudoaneuyrsm
Intrapulmonary lymph nodes
Inflammatory
Lung cancer
Metastasis
Carcinoid
Lymphoma

11. Metastatic Melanoma

12. Metastatic Colon Cancer

13. AVM

14. Hamartoma

15. Intrapulmonary Lymph Node

17. Intrapulmonary Lymph Node
Location
Subcarinal
Peripheral, sub pleural
Shape
Trianglular or angular
Elliptical
Semicircular

18. Describe Lesion Calcifications Fat Vascular Lesion
Intrapulmonary Lymph Node
Size
Morphology
Round, Lobulated, speculated
Solid, subsolid, Ground Glass

19. Calcification
Benign
Malignant

20. Malignancy Risk Factor
Suspicious morphology
Upper Lobe Location
Multiple nodules

21. Fleischner Society Guidelines est. 1969
Founded by 8 radiologist in 1969
International, multidisciplinary medical society for thoracic radiology
Meet annually
12 radiologist on working group for updating guidelines based on best evidence available

22. 2017 Fleischner Society Guidelines
Morphology and size
Solid
<6 mm
6-8 mm
>8 mm
Ground Glass or Part Solid
>6 mm

23. RISK: High vs Low low risk patients: HIGH risk patients:
Minimal or absent history of smoking and or other known risk factors
HIGH risk patients: 
history of smoking
Other known risk factors
First degree relative with lung cancer, or exposure to asbestos, radon, uranium

24. Solitary nodule: < 6 mm

25. Solid Nodule 6-8 mm

26. Solid Nodule

28. Solid Nodule >8 mm If Resolved Decreased in size Unchanged
Likely infection and no further work up needed
Decreased in size
Likely infection but needs follow up to resolution
Unchanged
Workup
PET Imaging
FOB, TTNB, Sx

29. Multiple Nodules Size Low Risk High Risk < 6 mm
No Routine Follow Up
Optional CT at 12 months
6-8 mm
Follow Up in 3-6 months
Consider further follow up at months
Follow up in 3-6 Months
Then at months if no change
> 8 mm
Follow up at 3-6 months then consider at months if no change
Follow up at 3-6 months then at months if no change

30. Subsolid nodules

31. Solitary GGN: < 6 mm

32. Solitary GGN < 6 mm

33. Solitary GGN: > 6 mm

34. Solitary GGN: > 6 mm

35. Part solid nodule: < 6 mm

36. Part solid nodule: >6 mm

37. Part solid or multiple nodule: > 6 mm

38. Subsolid Nodule Pure ground glass nodule or part solid nodule
Solitary or multiple nodules
May be infectious
Assumed to be adenocarcinoma in situ (AIS) formerly referred to bronchioloalveolar (BAC)
Part solid more likely to be malignant

39. Lung Adenocarcinomas Premalignant Malignant
Atypical Adenomatous hyperplasia
Adenocarcinoma in situ
Malignant
<5 mm minimally invasive adenocarcinoma
>5 mm Invasive adenocarcinoma

40. Use the correct calculator
LDCT SPN:
Incidental SPN:

42. Immunohistochemically Staining
Nodule
Mutation Analysis
Immunohistochemically Staining
Biopsy
Tumor
NSCLC
Adenocarcinoma
Squamous
SCLC
Driver Mutations:
EGFR
ALK (FISH)
MET
ROS

43. Obtaining Tissue Transbronchial Needle Aspiration (TBNA)
Sensitivity 78% (14-100%)
Specificity 100%
FALSE NEGATIVE 28% (0-66%)
If negative, evaluate (pre biopsy) pretest probability of cancer in context of Sn 78% with FN rate 28%
Higher with navigational bronchoscopy
Average Sn 77% and FN rate 22%
Detterbeck FC, et al. Chest. 2007;132:202S-220S.

44. Go for radiographic staging lesion
Distant mets (liver, adrenals, supraclavicular LN, bone mets)
Careful with bone mets bc with processing cannot do genetic tests
Please, Please , Please do not have IR do biopsy if they have mediastinal or hilar lymphadenopathy
IR biopsy if in peripheral ¼-1/3 of lung zone
IF UNSURE CALL, IT’S FREE AND SAFE FOR PATIENT

45. EBUS W or W/O ROSE Molecular Testing (KRAS, EGFR an ALK)
Achieved in 85% (108/126)
90% Successful in EBUS PLUS ROSE
80% Successful in EBUS Alone
18 Failures (6 EBUS+ROSE; 12 EBUS Alone)
Pathology failure (0 EBUS+ROSE, 6 EBUS Alone)
EBUS+ROSE more likely to have bronchoscopy terminated after single biopsy site (59% vs 44%)
EBUS+ROSE prevents need for repeat diagnostic procedure for molecular testing in 1:10 patients
Trisolini, et al, Chest 2015; 148:

46. NSCLC 2012
Adapted from W. Pao and N Girard, Lancet Oncol, 2011

47. Adapted from W. Pao and N Girard, Lancet Oncol, 2011

48. Actionable Mutations

49. Stage IV NSCLC

50. Current Molecular Based Therapies
EGFR Inhibitors
ALK inhibitors
Immune Check Point Inhibitors
Anti-PD Anti-PD-L1
Erlotinib
Rociletinib
Osimertinib
Ceritinib
Alectinib
Brigatinib
Loratibnib
Nivolumab
Pidizumab
Pembrolizumab
MDX 1105
MPDL3280A
MEDI4736
MSB C

51. Mutation Changes Treatment and Outcomes
KRAS mutation cases/year
EGFR mutation 1800 cases/ year
EML4-ALK 9000 cases/year (FISH)
Median Survival Time
260 driver mutations treated with targeted therapy
Median Survival Time 3.5 years (42 months)
318 driver mutations NOT treated with targeted therapy
Median Survival Time 2.4 years (28 Months )
360 with no driver mutation
Median Survival Time of 2.1 years (25 months)
Kris et al. JAMA 2014;311:

52. BKM120 (P13k inh) or rapamycin (mTOR/EGFR inh)
Acquired Mutation
Driver Mutation
Targeted Therapy
Acquire Mutation
Directed Therapy
EGFR
Gefitinib, Erlotinib
T790M
Osimertinib
ALK
Crizotinib
C1156Y, L1196M
Alectinib
PIK3CA NS
BKM120 (P13k inh) or rapamycin (mTOR/EGFR inh)

53. Resistance
Nature Rev Clin Oncol 2013; 10:

54. Osimertinib EGFR Resistance
Progressed
1st Line TKI
127
With T790M Mutation
PFS 9.6 Months 61
Without T790M Mutation
PFS 2.8 months
Osimertinib
Janne, et al. NEJM 2015; 372:1689

55. MET 5% of patients with acquired resistance to EGFR TKI
Cabozantinib + erlotinib
MET/RET/VEGFR + TKI
ORR 9% (35 patients)
INC280 + erlotinib
MET+ TKI
ORR 15% (41 patients)
Crizotinib + dacomitinib
ALK/MET inhibitor + pan-HER inhibitor
Stage 1

56. PIKCA 5% EGFR TKI develop PIK3CA MK 2206 (AKT inhibitor) ORR 9%
Erotinib + BKM120 (P13K inhibitor) active study
Rapamycin (mTOR)/EGFR inhibition active study

57. HER2 Amplification 12% EGFR mutations Afatinib + Cetuximab ORR 30%
HER2 + EGFR inhibitor

58. ALK Positive Lung Cancer
Conclusions
Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC.

59. Refractory ALK Alectinib + Crizotinib 138 patients (84 brain mets)
DOR 11.2 Months
CNS control 83% DOR 10.2 months
35 ORR 57%
12 month cumulative CNS progression rate 25%
Non CNS cumulative progression 33%
Ou, et al. J Clin Oncol 2016; 34:

60. ALK Extended Survival 90 patients ALK and brain mets
Radiotherapy (SRS or WBRT)
86 Received TKIK
Median survival after brain mets 49.5 months
CNS PFS 11.9 months
Johung KL. J Clin Oncol 2016; 34:

61. Immune Check Point Inhibitors Anti-PD1 or Anti-PD-L1 inhibitors
Postow et al J Clin Oncol 2015; 33:

62. Nivolumab 2nd line Squamous Cell
272 patients nivolumab 3mg/kg Q 2 wks vs docetaxel 75mg/m2 Q 3 weeks
Nivolumab (anti-PD-1)
Better 1 year survival 42 vs 24%
Better Response Rate 20% vs 9%
Better tolerated
Brahmer, et al. NEJM 2015;373:123

63. Should we repeat biopsy each time progresses on targeted therapy?
Resistance Testing
Should we repeat biopsy each time progresses on targeted therapy?

64. Liquid Biopsy Tumor Cells Release Free DNA into the blood
tumors need to contain ~50 million malignant cells
(PET positive 7-10mm ~1 billion cells)
circulating tumor cells (CTCs) and nucleic acids including cell-free RNA, microRNA, and circulating cell-free DNA (cfDNA), of which a subset may represent circulating tumor DNA
Target known oncogenic mutations
Blood Sample can Identify both genetic and epigentic aberration of cancers
Systematically track genomic changes
Nature Rev Clin Oncol 2013; 10:

65. Crowley E et al Nat Rev 2013; 10:472-484

66. Sholl et al Arch Pathol Lab Med 2016 doi: 10.5858/arpa.2016-0163-SA

67. Consensus Statement
Liquid biopsy has not been validated for lung cancer diagnosis
Lower sensitivity could lead to significant diagnostic delay
Clinical utility remains unproven
Concerns
Many lung cancers do not have a tumor-specific mutational profile
sensitivity of existing liquid biopsy approaches means that a negative result (especially FN) may lead to delay in a cancer diagnosis
False positive results may occur with detection of mutations (such as in RAS genes or TP53) from coincident marrow-derived clonal disorders
Incidental findings may lead to mischaracterization of a concomitant solid malignancy
Clinical Applications
Resistance mutation detection from plasma cfDNA is an appealing alternative to rebiopsy
Sholl et al Arch Pathol Lab Med 2016 doi: /arpa SA

68. Work Cited American Cancer Society, Cancer Statistics; 2015
Wender et al CA Cancer J Clin 2013
Detterbeck FC, et al. Chest. 2007;132:202S-220S.
Yamus et al, Ann ATS 2013;10:636
Trisolini, et al, Chest 2015; 148:
Adapted from W. Pao and N Girard, Lancet Oncol, 2011
Kris et al. JAMA 2014;311:
Postow et al J Clin Oncol 2015; 33:
Nature Rev Clin Oncol 2013; 10:
Crowley E et al Nat Rev 2013; 10:
Sholl et al Arch Pathol Lab Med 2016 doi: /arpa SA
Cernomaz et al BMC Pulonary Medicine; :88