SPN and Lung Cancer Adam J. Hayek, DO - PowerPoint Presentation

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SPN and Lung Cancer

Adam J. Hayek, DO

PGY-6

Pulmonary and Critical Care Fellow

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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

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Cancer Statistics 2015

American Cancer Society,

Cancer Statistics; 2015

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Survival Trend

Primary Site

New Cases (n)

Deaths (n)

5- Year Survival

1975-1977

5 Year Survival

2004-1010

ΔProstate220,80027,54068%99%+31%Breast234,19040,73075%91%+16%Colorectal132,70049,70051%65%+14%Lung221,200158,04012%18%+6%Pancreas48,96040,5603%7%+4%

American Cancer Society,

Cancer Statistics; 2015

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Survival Trend

Primary Site

New Cases (n)

Deaths (n)

5- Year Survival

1975-1977

5 Year Survival

2004-1010

ΔProstate220,80027,54068%99%+31%Breast234,19040,73075%91%+16%Colorectal132,70049,70051%65%+14%Lung221,200158,04012%18%+6%Pancreas48,96040,5603%7%+4%

American Cancer Society,

Cancer Statistics; 2015

Why??

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Lung Cancer Survival

Symptomatic

Lung Cancer generally advanced stage disease and not currently curable

Lung Cancer at Diagnosis: 2002-2008

226,000 New Diagnosis

Localized 15%

Regional 22%

Distant 56%

Wender et al CA Cancer J Clin 2013

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Screening

Primary Site

New Cases (n)

Deaths (n)

5- Year Survival

1975-1977

5 Year Survival

2004-1010

ΔProstate220,80027,54068%99%+31%Breast234,19040,73075%91%+16%Colorectal132,70049,70051%65%+14%Lung221,200158,04012%18%+6%American Cancer Society, Cancer Statistics; 2015

PSA

Screening

Mammography

Colonoscopy

LDCT CMS 2/15/2015

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National Lung Cancer Screening Trial (NLST)

Age 55-74

Smoker

Former smoker quit < 15

yrs

ago

30

pk

yr20% reduction in lung cancerYoung, et al. Subgroup analysis of 18,714 with spirometry 34% had COPD accounting for 52% cancer casesYoung, et al. AJRCCM 2015;192:1060-1067

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SPN

Found round or oval area of increased opacity

Spiculated

or lobulated

Can be non solid, part solid or solid

<3 cm

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DDx

Benign:

Pneumonia

Granuloma

Hamartoma

AVM

Pulmonary artery

pseudoaneuyrsm Intrapulmonary lymph nodes InflammatoryMalignant: Lung cancer Metastasis Carcinoid Lymphoma

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Metastatic Melanoma

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Metastatic Colon Cancer

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AVM

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Hamartoma

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Intrapulmonary Lymph Node

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Intrapulmonary Lymph Node

Location

Subcarinal

Peripheral, sub pleural

Shape

Trianglular

or angular

Elliptical

Semicircular

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Describe Lesion

Calcifications

Fat

Vascular Lesion

Intrapulmonary Lymph Node

SizeMorphology

Round, Lobulated, speculated

Solid,

subsolid, Ground Glass

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Calcification

Benign

Malignant

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Malignancy Risk Factor

Suspicious morphology

Upper Lobe Location

Multiple nodules

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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

https://fleischnersociety.org

/

Slide22

2017 Fleischner Society Guidelines

Morphology and size

Solid

<6 mm

6-8 mm

>8 mm

Ground Glass or Part Solid

<6 mm

>6 mm

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RISK: High vs Low

low

risk patients

:

Minimal

or absent history of smoking and or other known risk factorsHIGH risk

patients:

 

history of smoking Other known risk factors First degree relative with lung cancer, or exposure to asbestos, radon, uranium

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Solitary nodule: < 6 mm

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Solid Nodule 6-8 mm

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Solid Nodule

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Solid Nodule >8 mm

If Resolved

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

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Multiple Nodules

Size

Low Risk

High Risk

< 6 mm

No Routine Follow Up

Optional

CT at 12 months

6-8 mmFollow Up in 3-6 monthsConsider further follow up at 18-24 monthsFollow up in 3-6 MonthsThen at 18-24 months if no change> 8 mmFollow up at 3-6 months then consider at 18-24 months if no changeFollow up at 3-6 months then at 18-24 months if no change

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Subsolid nodules

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Solitary GGN: < 6 mm

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Solitary GGN < 6 mm

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Solitary GGN: > 6 mm

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Solitary GGN: > 6 mm

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Part solid nodule: < 6 mm

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Part solid nodule: >6 mm

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Part solid or multiple nodule: > 6 mm

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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

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Lung Adenocarcinomas

Premalignant

Atypical Adenomatous hyperplasia

Adenocarcinoma in situ

Malignant

<5 mm minimally invasive adenocarcinoma

>5 mm Invasive adenocarcinoma

Slide40

Use the correct calculator

LDCT SPN:

https

://brocku.ca/node/21910/done?sid=137297

Incidental SPN:

http

://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk

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Nodule

Driver Mutations:

EGFR

ALK (FISH)

MET

ROS

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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.

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Go for radiographic staging lesion

Distant

mets

(liver, adrenals, supraclavicular LN, bone

mets

)Careful with bone

mets

bc with processing cannot do genetic testsPlease, 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 zoneIF UNSURE CALL, IT’S FREE AND SAFE FOR PATIENT

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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: 1430-1437

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NSCLC 2012

Adapted from W.

Pao

and N Girard, Lancet

Oncol

, 2011

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Adapted from W.

Pao

and N Girard, Lancet

Oncol

, 2011

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Actionable Mutations

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Stage IV NSCLC

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Current Molecular Based Therapies

EGFR Inhibitors

ALK inhibitors

Immune Check Point Inhibitors

Anti-PD-1

Anti-PD-L1

Erlotinib

RociletinibOsimertinibCeritinibAlectinibBrigatinibLoratibnibNivolumabPidizumabPembrolizumabMDX 1105MPDL3280AMEDI4736MSB0010718C

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Mutation Changes Treatment and Outcomes

KRAS mutation 36000 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 mutationMedian Survival Time of 2.1 years (25 months)Kris et al. JAMA 2014;311:1998-2006

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Acquired Mutation

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Resistance

Nature Rev

Clin

Oncol

2013; 10:472-484

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Osimertinib EGFR Resistance

Osimertinib

Janne

, et al.

NEJM 2015; 372:1689

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MET

5% of patients with acquired resistance to EGFR TKI

Cabozantinib

+

erlotinib

MET/RET/VEGFR + TKI

ORR 9% (35 patients)

INC280 +

erlotinib MET+ TKIORR 15% (41 patients)Crizotinib + dacomitinibALK/MET inhibitor + pan-HER inhibitor Stage 1

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PIKCA

5% EGFR TKI develop PIK3CA

MK 2206 (AKT inhibitor) ORR 9%

Erotinib

+ BKM120 (P13K inhibitor) active study

Rapamycin (mTOR

)/EGFR inhibition active study

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HER2 Amplification

12% EGFR mutations

Afatinib

+

Cetuximab

ORR 30%HER2 + EGFR inhibitor

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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.

Slide59

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; 34:661-668

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ALK Extended Survival

90 patients ALK and brain

mets

Radiotherapy (SRS or WBRT)

86 Received TKIKMedian survival after brain

mets

49.5 months

CNS PFS 11.9 months Johung KL. J Clin Oncol 2016; 34:123-129

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Immune Check Point Inhibitors Anti-PD1 or Anti-PD-L1 inhibitors

Postow et al J Clin Oncol 2015; 33:1974-82

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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

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Resistance Testing

Should we repeat biopsy each time progresses on targeted therapy?

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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 DNATarget known oncogenic mutations Blood Sample can Identify both genetic and epigentic aberration of cancersSystematically track genomic changes Nature Rev Clin Oncol 2013; 10:472-484

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

Slide66

Sholl et al

Arch

Pathol

Lab

Med 2016

doi

: 10.5858/arpa.2016-0163-SA

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Consensus Statement

Liquid biopsy

has not been validated for lung cancer

diagnosis

Lower sensitivity

could lead to significant

diagnostic delay

Clinical

utility remains unprovenConcernsMany lung cancers do not have a tumor-specific mutational profilesensitivity of existing liquid biopsy approaches means that a negative result (especially FN) may lead to delay in a cancer diagnosisFalse positive results may occur with detection of mutations (such as in RAS genes or TP53) from coincident marrow-derived clonal disordersIncidental findings may lead to mischaracterization of a concomitant solid malignancyClinical Applications Resistance mutation detection from plasma cfDNA is an appealing alternative to rebiopsySholl et al Arch Pathol Lab Med 2016 doi: 10.5858/arpa.2016-0163-SA

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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: 1430-1437 Adapted from W. Pao and N Girard, Lancet Oncol, 2011Kris et al. JAMA 2014;311:1998-2006Postow et al J Clin Oncol 2015; 33:1974-82Nature Rev Clin Oncol 2013; 10:472-484Crowley E et al Nat Rev 2013; 10:472-484Sholl et al Arch Pathol Lab Med 2016 doi: 10.5858/arpa.2016-0163-SACernomaz et al BMC Pulonary Medicine; 2016 16:88