TARGETED THERAPY,IMMUNO THERAPY

1. LUNG CANCER
VIJAY

2. • Lung cancer is one of the most frequent
malignancy in the world
• It is the most common solid tumour type
,after breast cancer in women and
prostate cancer in men
• It remains the most common cancer
related death in men and second in
women.
• Tobacco the most important risk factor
cause 71% of lung cancer deaths

3. • In recent past years relative increases in
incidence of adenocarcinoma
- changes in the smoking behaviour
- use of filtered cigarettes with low content of
tar and nicotine.

4. Risk factors
• Tobacco smoking (active)
• Environmental tobacco smoke exposure
• Pulmonary diseases
COPD,IPF,SS-ILD, Pneumoconiosis
• Systemic diseases: HIV
• Air pollution (indoor and out door)
- Domestic cooking fuels
- Petroleum product combustion exhaust exposure
• Environmental exposure
- Radon, Arsenic, Nickel, Chromium, Asbetos and Silica
• Dietary factors
-Alcohol Consumption,
-Intake of vitamins, fruits and vegetables
• Hormonal therapy
• Genetic factors
- Familial
-Specific gene abnormalities(nonhereditary)

5. BIOLOGY OF LUNG CANCER
• Most clinically significant acquired genetic
abnormalities in lung cancer are the
mutation of the EGFR and the Anaplastic
lymphoma kinase (ALK) fusion.
• EGFR mutations occur in approximately
20% of lung cancer patients and are
primarily in exons 19 and 20 (L858R
point mutants

6. • ALK fusions have been reported in 3% to
7% of lung cancer patients and are
associated with a 57% response to
Crizotinib.
• The EGFR and ALK abnormalities are
non– overlapping. Interestingly, both
EGFR mutations and ALK fusions are
associated with younger age, light (<10
pack-year) and non smokers and
adenocarcinoma histology.

7. HISTOPATHOLOGY
• Most lung cancers are classified as two
major types:
• Small cell lung carcinoma (SCLC)
• non – small cell lung carcinoma (NSCLC)
NSCLCs are more common
Squamous cell carcinoma
Adenocarcinoma,
Large cell carcinoma

8. NSCLC vs SCLC
NSCLC SCLC
Incidence 85% 15%
Origin Epithelial cells of the
lung
Nerve producing cells of the lung (bronchi)
Classification  Squamous cell
 Large cell
 Adenocarcinoma
 Limited stage
 Extensive stage
Metastatic
potential
Less than SCLC Rapid metastatic potential
Treatment  Surgery
 Chemotherapy
 Radiotherapy
 Chemotherapy
 Radiotherapy
5 year survival  Stage I : 57 – 67%
 Stage II : 39 – 55%
 Stage III : 5 – 25%
 Stage IV : < 1%
 Limited 20%
 Extensive < 1%

9. • SCLC grows quickly and has often already
reached an advanced stage when it is
diagnosed.
• NSCLC, on the other hand, is more slow
growing and may be diagnosed at a stage
when it can be surgically removed

10. SQUAMOUS CELL CARCINOMA
• Highly associated with smoking.
• Arise from the epithelial layer of the bronchial wall
and later extends beyond the bronchial mucosa as it
becomes invasive.
• Typically occur as central mass but approximately 25%
are located peripherally and 5% show central
cavitation
• Associated with Hypercalcemia (produces PTHrP)
• Histologically 2 features are important for diagnosis
-Keratinisation and intercellular bridges
• WHO 2015 categorises it to keratinising, non
keratinising and basaloid variants.

11. ADENOCARCINOMA
• Most common lung cancer in nonsmokers and
females
• Commonly present as peripheral nodule and rarely
shows cavitations.
• Adenocarcinoma can form gland like structures and
produce mucus
• Subtypes include Lepidic predominant (formerly
known as BAC), Acinar predominant, Papillary
predominant, Solid predominant and Micro papillary
predominant.
• Associated with Hypertrophic osteoarthropathy
(clubbing)
• 80-90% of Adenocarcinoma shows more than one
histological pattern
• Of these patterns, the solid and micro papillary
patterns in adenocarcinoma may predict a worse
prognosis

12. • Lepidic, acinar, and papillary predominant
tumors had intermediate prognosis.
• The international panel and NCCN
recommend that all patients with
adenocarcinoma be tested for EGFR
mutations and Anaplastic lymphoma
kinase (ALK) gene rearrangements

13. Criteria to diagnose Adenocarcinoma
• Tumour architecture
• Mucin strain :
• Immunihistochemistry
• For Adenocarcinoma:TTF-1,keratin 7 and
Napsin
• Of these TTF 1 is considered single best
marker as it serves as a pneumocyte
marker that help to conform a primary
lung origin in 75 -80% of lung
adenocarcinomas.

14. LARGE CELL CARCINOMA
• 10% of lung cancers
• Strong association with smoking.
• Tend to occur peripherally
• Highly anaplastic undifferentiated tumor.
• Poor prognosis
• Less responsive to chemotherapy; removed
surgically.
• Histological subtype is often difficult to accurately
diagnose owing to an abundance of necrotic tissue
and a poor degree of differentiation, diagnosis requires
an adequate tissue specimen..
• Large cell tumors stain positively for neuroendocrine
markers such as chromogranin a and
synaptophysin.

15. Small Cell Lung Carcinoma
• Also called Oat cell carcinoma or Small cell
neuroendocrine carcinoma
• Undifferentiated - very aggressive.
• Centrally located
• strongly associated with cigarette smoking
• Managed with chemotherapy +/– radiation.
• Shows large areas of multifocal necrosis
• Tumor cells are of pulmonary neuroendocrine cell
origin.
• Released factors are often associated with
paraneoplastic syndromes.
• Neurologic and endocrine paraneoplastic
syndromes are associated with SCLC

16. • May produce ACTH (Cushing syndrome),
SIADH, or Antibodies against presynaptic
Ca2+ channels (LambertEaton myasthenic
syndrome) or neurons (paraneoplastic
myelitis, encephalitis, subacute cerebellar
degeneration

17. IMMUNOHISTO CHEMISTRY(IHC)
• With the advent of different therapies for adenocarcinoma
and squamous cell carcinoma, it has become crucial to
distinguish them on small biopsies and cytologic specimens
when the morphologic features of each of these types of
carcinoma may not be evident
• IHC stains useful in the diagnosis of adenocarcinoma include
TTF-1 (Thyroid transcription factor-1, a protein that
regulates transcription of genes specific for the thyroid, lung,
and diencephalon) and Napsin A (a member of the aspartic
protease family, expressed in normal lung and kidney,
adenocarcinomas from lung, and some renal carcinomas) .
• Squamous cell carcinoma markers include high-molecular-
weight Cytokeratins, such as CK5/6, and p63 (a member of
the p53 family of transcription factors).
• Neuroendocrine markers include CD56 or neural cell
adhesion molecule (NCAM), Synaptophysin, and
Chromogranin

18. • IHC also helpful in distinguishing primary lung tumors
from malignancies metastatic to the lung.
• This is especially true for distinguishing primary lung
adenocarcinomas and metastatic adenocarcinomas.
TTF-1, identified in tumors of thyroid and pulmonary
origin, stains more than 70% of pulmonary
adenocarcinomas.When positive, TTF-1 is a reliable
indicator of a primary lung cancer provided a
thyroid primary has been excluded. A negative TTF-
1, however, does not exclude the possibility of a lung
primary tumor.
• TTF-1 can also be positive in neuroendocrine tumors
of pulmonary and extrapulmonary origin

19. CLINICAL FEATURES
• 7% to 13% patients are asymptomatic at the time of initial diagnosis.
• Cough is the most frequently presenting symptom
Endobronchial or parenchymal involvement by the primary tumour
regional lymph node enlargement
• post obstructive complications.
• Breathlessness
• Anorexia and weight loss
• Chest discomfort and pain
• -may indicate pleural involvement or direct tumor invasion of the
chest wall or thoracic cage.
• Hemoptysis- cardinal symptom of lung cancer-bronchial mucosa ulceration
• Hoarseness due to laryngeal nerve palsy, which occur in 2% to 18% of lung
cancer patients. This is more commonly seen with left-sided tumors , which
can involve the recurrent laryngeal nerve as it loops under the aortic arch.
• Lung cancer accounts for up to 75% of all cases of superior vena cava
(SVC) syndrome due to local compression or invasion. Signs and
symptoms of SVC syndrome include swelling of the face, neck, upper torso
and arms, and dyspnea.Up to 4% of patients with NSCLC and 10% of
patients with SCLC can develop SVC syndrome.

20. • Dysphagia - extrinsic compression of the esophagus
due to bulky mediastinal disease, particularly
subcarinal lymph node, or it can result from direct
esophageal invasion.
• Central tumors such as Squamous cell carcinoma
may cause airway obstruction resulting in a localized
or unilateral wheeze, atelectasis, or post obstructive
pneumonia.
• Cancers arising in the lung apex (superior sulcus
tumors) can present with the Pancoast syndrome.
- Characteristic signs and symptoms include
shoulder pain due to invasion of the brachial plexus
and/or ribs and vertebrae, upper extremity weakness
and paresthesias, and Horner syndrome (unilateral
ptosis, meiosis, and lack of facial sweating on the
involved side) due to compression or invasion of the
sympathetic chain.

21. 8th Edition of the TNM
Classification for Lung Cancer

22. T-tumour
Proposed (TNM
8th)
Up to 1 cm: T1a
>1-2 cm: T1b
>2-3 cm: T1c
>3-4 cm: T2a
>4-5 cm: T2b
>5-7 cm: T3
>7 cm: T4
Previous (TNM
7th)
T1a
T1a
T1b
T2a
T2a
T2b
T3

23. T – Primary Tumour
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 3 cm or less in greatest diameter surrounded by lung or visceral pleura, without
evidence of main bronchus
T1a(mi) Mininally invasive adenocarcinoma
T1a Tumour 1 cm or less in greatest diameter
T1b Tumour more than 1 cm but not more than 2 cm
T1c Tumour more than 2 cm but not more than 3 cm
T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features:
Involves main bronchus (without involving the carina), invades visceral pleura, associated
with atelectasis or obstructive pneumonitis that extends to the hilar region
T2a Tumour more than 3 cm but not more than 4 cm
T2b Tumour more than 4 cm but not more than 5 cm
T3 Tumour more than 5 cm but not more than 7 cm or one tha directly invades any of the following:
chest wall, phrenic nerve, parietal pericardium, or associated separate tumour nodule(s)
in the same lobe as the primary
T4 Tumours more than 7 cm or one that invades any of the following: diaphragm, mediastinum,
heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body,
carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary

24. N – Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes
and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene or supraclavicular lymph node(s)
M – Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural
or pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extrathoracic metastases in one or several organs

25. TNM staging overview
STAGE I All T1 tumors and T2 tumors without lymph node
metastasis
STAGE II T1 and T2 tumors with involvement of ipsilateral hilar
nodes
STAGE IIIA Ipsilateral mediastinal disease
IIIB More widespread disease
STAGE IV Unresectable disease

27. chemotherapy
• Platinum based chemotherapy remain an
important component of the management
protocol for all patientss with NSCLC –
early,locally advanced,and metastatic
• For advanced/metastatic the current
standard of care is chemotherapy

28. • Chemotherapy for lung cancer is given in the following
clinical scenario
 As adjuvant following surgical resection (Stage 1B and stage
II)
 As neoadjuvant therapy to downstage the tumour before
surgical resection(Stage IIIA)
 Along with radiotherapy (concurrent or sequential ) in locally
advanced lung cancer(Stage III A and Stage III B)
 Palliative chemotherapy in metastatic lung cancer(Stage IV
 Currently chemotherapy given with Platinum agent combined
with 3 rd generation agents (Taxanes,Gemcitabine
,pemetrexed and vinorelbine)

29. Surgery : Types
• Radical operation:
– Pneumonectomy.
• Lung Conservation:
– Lobectomy.
– Sleeve resection.
– Wedge resection.
– Segmentectomy.
• Mediastinal lymph node dissection:
– Provides complete nodal staging.
– Identifies patients who require adjuvant
radiotherapy.
– Improves survival.
– Improves local control.

30. Targeted therapy
• Targeted therapy refers to treatment with pharmaceuticals
agents that affect a known molecular target in the cancer cell
or tumour microenvironment
• The development of targeted therapy for specific gene
mutations has resulted in the reality of individually tailored
therapy. Subtype analysis of NSCLC has come full circle now
that epidermal growth factor receptors (EGFR), anaplastic
lymphoma kinase (ALK), and c-ROS oncogene 1 (ROS1)
mutations are not only identifiable but their targeted treatment
results in responses better than that with standard
chemotherapy

32. The two most commonly used first-line
EGFR-TKIs are erlotinib and gefitinib, both
of which are available for use in India.
These agents reversibly bind to the
intracellular ATP binding region of the
EGFR and competitively inhibit the binding
of ATP.

33. Erlotinib
• Dose 150mg per day, orally
• It is metabolized by Liver.
• FDA approved erlotinib in 2013 in pt with
locally advanced and metastatic NSCLC
who has failed atleast one prior
chemotherapy regimen.
• Side effects :
Rash
Interstitial pneumonitis, diarrhea
GI perforation, SJ syndrome, BOOP,
pulmonary fibrosis are rare side effects

34. Gefitinib
• In 2015, the FDA approved gefitinib as a
first-line treatment for metastatic NSCLC ,
which are positive for EGFR gene
mutation.
• Dose 250mg per day orally
• Side effects
• Rash, acne, diarrhea, stomatitis,
paronychia, asymptomatic elevation of
liver enzymes

35. IMMUNOTHERAPY
• By the time that most lung cancer patients are
diagnosed, the disease is already advanced, or at
stage iiib/IV or higher—when surgery, chemo, and
radiation are only minimally effective. For this
reason, new, more advanced treatment technology
is badly needed for patients facing an advanced
lung cancer diagnosis.
• Immunotherapy drugs stimulate a person’s own
immune system to recognize and destroy cancer
cells more effectively
• Immunotherapy has the potential to benefit lung
cancer patients for whom more conventional
chemotherapy or radiation treatments are
ineffective.

36. • Immune checkpoint inhibitors
• An important part of the immune system is its ability to keep itself from
attacking normal cells in the body. To do this, it uses “checkpoints” –
molecules on immune cells that need to be turned on (or off) to start an
immune response. Cancer cells sometimes use these checkpoints to avoid
being attacked by the immune system. But newer drugs that target these
checkpoints hold a lot of promise as cancer treatments.
• Nivolumab and pembrolizumab target PD-1, a protein on immune
system cells called T cells that normally helps keep these cells from
attacking other cells in the body. By blocking PD-1, these drugs boost the
immune response against cancer cells. This can shrink some tumors or
slow their growth.
• Atezolizumab targets PD-L1, a protein related to PD-1 that is found on
some tumor cells and immune cells. Blocking this protein can also help
boost the immune response against cancer cells.
• These drugs can be used in people with certain types of NSCLC whose
cancer starts growing again after chemotherapy or other drug treatments.
• Pembrolizumab can also be used as the first treatment in some people,
either along with or instead of chemo.

37. Paraneoplastic syndromes

38. Paraneoplastic syndromes
• A group of clinical disorder that are associated with malignant
diseases, not directly related to the physical effects of primary
or metastatic tumour are known as paraneoplastic
syndromes syndromes .
• It occur in 10% of patients with lung cancer
• The size of the primary tumour has no impact on the extent of
para neoplastic symptoms
• These paraneoplastic syndrome can preceed the diagnosis
of malignant disease ,may occur late in the course of the
illness or herald the first sign of recurrence of lung cancer
• The most common tumor producing paraneoplastic syndrome
in humans are lung cancer
• Neurologic and endocrine paraneoplastic syndromes are
associated with SCLC.

39. • Paraneoplastic syndrome are more frequently associated
with small cell cancer but can be seen with any histological
type
• Cushing syndrome
• lung cancer is a most common source of ectopic secretion
of ACTH among non pituitary neoplasm's biologically
active ACTH resulting in adrenal gland hyperplasia and
hyperfunction is usually produced by small cell carcinoma
(80%) , uncommonly by carcinoid tumor (10% ) and
adenocarcinoma (5%) of the lung
• increased serum levels of ACTH may be detectable in up
to 50% of patient with bronchogenic carcinoma diagnosis is
usually suggested by features of acute hypercortisolism
such as hypertension, hyperglycemia and hypokalemic
alkalosis.
• DIAGNOSIS is conformed by demonstration of plasma
ACTH levels of more than 22 p mol/L,plasma cortisol of
more than 600 nmol/L and 24 hour urinary free cortisol of
more than 400 nmol/l,which does not supress after a high
dose of dexamethasone

40. Hypercalcemia
• Overal 10% of lung cancers have hypercalcemia which
usually complicate squamouscell ca that secrete PTH-rp
• The diagnosis of PTH-rP associated paraneoplastic
syndrome is considered if serum calcium level exceed
10.5 mg/dl
• Hypercalcemia initially produce
nausea,vomitings,constipation ,polyuria,and nocturia
resulting in hypovolemia and renal failure
• As serum calcium goes up patient may become
confused and drowsy and ultimately coma may
supervene misleading the physician towards intracranial
metastasis

41. SIADH
• Mainly associated with small cell lung cancer
• SCLC cells produce polypeptide hormones, including
vasopressin (antidiuretic hormone [ADH]) and
adrenocorticotropic hormone (ACTH), which cause
hyponatremia of malignancy (ie, syndrome of
inappropriate ADH secretion [SIADH]) and Cushing
syndrome, respectively
• In patients with SCLC, SIADH occurs more frequently
than Cushing syndrome.
• Treatment for SIADH includes fluid restriction (which is
difficult for patients because of increased thirst),
demeclocycline, or vasopressin receptor inhibitors
(ie,conivaptan, tolvaptan).

42. • Lambert-Eaton myasthenic syndrome
present with proximal leg weakness
• that is caused by antibodies directed
against the voltage-gated calcium
channels.

43. thanku
• Thanku