Lecture 2 - Lung Cancer
Epidemology Overview
Lung cancer is the leading cause of cancer-related deaths worldwide
Eastern Asia & Eastern Europe > higher incidence & higher mortality rates from lung cancer
Mortality and Lifestyle Factors
Regions with higher mortality > higher smoking rate, limited access to early detection or effective treatment
Epidemeology Overview — on Australia
A need for early detection and intervention to improve survival rates
Rankings in Cancer Incidence
Lung cancer ranks fourth among cancers in terms of cases but maintains the highest mortality rate.
Lung Anatomy and Cancer Development
Lung Structure Overview:
Sponge-like organ necessary for gas exchange.
Right lung has three lobes; left lung has two due to the heart's positioning > assymetrical > allows the heart to fit
Left
Airway Pathway:
Gas exchange:
Air enters through the trachea, travels to bronchi, and reaches alveoli
When cancer cells start growing > mess with this delicate system of gas exchange
Cancer begins in the airway — where the air flows through trachea, bronchi, brinchioles & alveoli > this is why it’s linked with smoking
Lung cancer disrupts the gas exchange mechanism, beginning often in the airway
Lung cancer — irritates & damages lung tissue > increases risk of mutations in the cells, cell lining & airway of lung
Cancer cell may first grow in bronchi > then spread & block the airway
Pumera > causes pain & makes it a lot harder to breathe
Lung protection & support
Pleura — double layered membrane that surrounds the lung > allows it to expand & contract without any friction
Diaphragm — big muscle underneath the lung > moves down when inhaling
Mediastinum — where the heart & vital organs are sitting > when the cancer spreads to lungs where the lymph nodes are > this is where the lung cancer cells will be growing > do not get diagnosed in early stage > when they get to this area > already late stage > it is only when it spreads that it will get picked up
Lung cancer — aggressive compared to other cancer types > ranked as #1 in mortality rate > infiltrates a lot of surrounding tissue & affect a lot of important structures — e.g. diaphragm & blood vessels
As the cancer continues to grow > block the airway > make it a lot harder to breathe > fluid buildup > affect the further lung function
Hallmarks of Lung Cancer
Genetic mutations influenced by carcinogen interactions lead to uncontrolled cell growth.
Formation of DNA adducts from environmental exposures (e.g., smoking).
Key Hallmarks:
Sustaining proliferation signaling.
Evasion of growth suppressors.
Genomic instability.
Resistance to cell death.
Emphasis on the need for understanding genetic factors in preventing and treating lung cancer.
Mutation & genomic alterations
When carcinogens do the damage > cause the mutation in key genes that are essential for controlling cell growth
Oncogenes — genes that promote growth
Tumour suppressor genes — genes that normally stop the cells from growing
Lung carcinogenesis
3 hallmarks that are important:
Sustaining proliferation signalling
Evading growth suppressor
Genomic instability
Will look at how medications will be targeting them in order to stop the growth of cancer
Risk Factors and Screening Procedures
Risk Factors:
Smoking, air pollution, familial history, and occupational exposures.
History of
sputum cytology — mucus under microscope
However, chest X-rays didn’t help reduce lung cancer deaths > only can see the tumour when in advanced stage > can’t see it in early stage
Screening Tools:
Historically involved chest X-rays; current recommendation favors low-dose computed tomography (CT).
National lung cancer screening programs implemented, emphasizing the importance of early detection.
Challenges:
False positives and potential for overdiagnosis.
Psychological burdens on patients.
Diagnostic Strategies
Common Symptoms:
Persistent cough, chest pain, weight loss, hemoptysis (coughing blood).
Diagnostic Procedures:
Chest X-rays, CT scans, PET scans for detail.
Various biopsy methods for confirming diagnosis.
Molecular Testing
Biomarkers are location-specific — matches with both type of the cancer & genetic mutation
Distribution of lung epithelial cells across the proximal & distal parts of the lung > tells how the cancer develops > the genetic material changes depending on where the cancer starts
Molecular Testing — PDL-1 Testing [NSCLC]
PDL-1 — sits on cancer cells > helps cancer cells to hide
PDL-1 > binds to PD-1 receptor on T cells > tells T cells to not attack the tumour growth > allows the cancer cell to keep growing without any checkpoint to stop it
higher PDL-1 expression > checkpoint inhibitors — e.g. nivolipomab & pembolucimab — are very well placed to counteract it
Immunotherapy — works by taking the brake off the immune system & tell the normal healthy T cells to destroy the tumour
Immunotherapy > gives the healthy T cells extra boost so that they know what to do
Molecular Testing — Driver Mutations
Squamous cell carcinoma — common in smokers, lives in central airway > PDL-1 testing is extremely important when it comes to it
Non-squamous histology — includes adenocarcinaoma& required a genetic teting to identify that
EGFR, ALK, KRAS & ROS live there
Look to where these mutations are > to have targeted therapy
Lung Cancer — Types
2 types of lung cancer:
Small cell — 10-15% of lung cancer cases
More aggressive than non-small cell > Moves very quickly to different parts of body > Metastisis in the brain
Strong link to smoking
Survival rate — low
Non-small cell — accounts for 80-85% of lung cancer
Adenocarcinoma — most common lung cancer
Happens to non-smokers, women, asian & young people
Starts from outer part of lung & then continues to move into the tiny airsacs which are responsible for gas exchange
Mutations involved — EGFR & KRAS
Normally leads to a positive outcome > have a medication that targets EGFR & KRAS inhibitors
Has better prognosis compared to the other types of lung cancer > can be detected earlier
Squamous cell carcinoma
Linked to smoking
Lives around central bronchi of lungs close to trachea
Highly aggressive > grow & spread extremely fast
Lead to fast blockage of airway > symptoms of shortness of breath, constant coughing
Therapies — radiotherapy & chemotherapy
Large cell carcinoma — undifferentiated
Rare
Highly aggressive form of lung cancer > quickly moves to different places in the organ > metastasis a lot faster & earlier >
Happen anywhere in the lung
Undifferentiated > cancer cells can go into the lung cells, but because they are undifferentiated > body will not have the system in place to kick it out
Lung Cancer — SCLC Staging
2 stages
Limited stage — more confined to one side of the chest
Extensive stage — already spread beyond the lung
Goals of Therapy
Treatment selection criteria:
Patient preference — willingness to undergo specific treatment
Tumour characteristics — type, size & stage of lung cancer
Small tumour > suitable for surgical resection
Larger tumour > chemotherapy, radiotherapy
Stage 1 tumours — surgically removed
Stage 4 tumours — require a combination of chemotherapy, immunotherapy or targeted therapy
Mutation status — when it comes to molecular testing for genetic mutations — e.g. EGFR, ALK, KRAS & RAS1 > crucial in determining whether the targeted therapy or immunotherapy will be effective > allows personalised treatment that targets the specific genetic alteration & driving the tumour
EGFR mutations — can be targeted with EGFR inhibitors
Treatment Options
Surgery — recommended for early-stage lung cancer > when the tumour is localised & has not spread to other parts of body
In stage 1 & 2 of lung cancer > surgical recession is one of the primary treatment options, especially when the cancer is confined one lung & can be surgically removed
One of the common surgery procedures — labectomy > removal of lobe of lung > or wedge resection — removal of some isolated portion of the lung
If surgery is not feasible because they are of advanced stage, or if cancer has spread to distant organs or vital structure > systemic therapies — e.g. chemotherapy, radiotherapy, immunotherapy may be more appropriate
Radiotherapy — used in situations where surgery cannot be used for tumour > to shrink down tumour or control tumour growth
Alleviates symptoms in advanced stages — e.g. pain or difficulty breathing > tumours can cause obstruction of airway
May sometimes be done before surgery > to reduce the risk of recurrence
Chemotherapy — involves the use of drugs to destroy cancer cells
Used when surgery is not an option, or when cancer has spread beyond the lungs
Can effectively target any rapidly dividing cancer cell, but it also affects the healthyc cells > lead to common side effects — e.g. fatigue, nausea, hair loss
Immunotherapy — key treatment for advanced stage lung cancer, especially though PD1/PDL-1 inhibitors
Useful in advanced non-small cell lung cancer
Its use is determined by the tumour PDL-1 expression levels or tumour mutational burden
These drugs work by blocking PD1/PDL-1 pathway > cancer cells use to evade the immune system
By enhancing the immune response > will help the immune system target & destroy the cancer cell
Molecular targeted therapies — designed to target specific genetic mutation or molecular pathways that drive tumour growth in non-small cell lung cancer > more personalised approach
EGFR inhibitior example — oscimitib > used for EGFR mutation
Supportive care — focuses on managing the symptoms & improving quality of life
Palliative care — aims at comfort, knowing the cancer won’t be curable > aim is to manage the symptoms & provide psychosocial support
Overview
Targeted therapy > allows for personalised therapy
EGFR mutation positive — mutations that are effective in inital stage before resistance develops
BRAF V600E positive — rare in lung cancer
Dabrafenib + Trametinib combination therapy — block MCP pathway > abnormally activated in tumours for BRAF V600E mutations
1st Line Therapy
Immunotherapy > tells the T cells to attack the tumour cells
1st line treatment > want some of the mutations to be present
Patients that should be considered — those that have poor performance starters > already have extensive metastisis in either side of the organ, have significant comorbidities, older age > lead to prognosis to be worse
…. potential rechallenge upon progression may occur if the disease progresses after initial treatment, where the patient may benefit from resuming treatment after a period of remission
Atypical responses:
Pseudoprogression — where tumour will initially appear to grow, will be detected by imaging, but later will shrink down > common for patients using immunotherapy, especially for PD-1 & PDL-1 inhibitors
Different to actual tumour growth > have time limit to growth before starting to shrink
Hyperprogression — where the disease will worsen very rapidly than expected after the start of treatment
Related to genetic mutations or immune system responding > require a treatment plan to be adjusted
Immunotherapy — effective in patients with high PDL-1 expression > one of the central treatment strategy for advanced or metastatic non-small cell lung cancer
Whether a patient needs monotherapy or combination therapy depends on the presentation or expression of some of the targeted treatment
If patient has high PDL-1 expression > monotherapy with PD1/PDL-1 inhibitors is recommended
Effective in controlling any tumour growth while having fewer side effects compared to chemotherapy
For combination therapies for patients with lwoer PDL-1 expression > combination of PDL-1 inhibitors with chemotherapy is effective
Works by leveraging the immune system’s ability to target cancer cells while using chemotherapy to shrink tumours & prevent further spread
Combiantion therapy improves response rates & survival in patients who might not respond well to monotherapy alone
Immunotherapy
Checkpoint inhibitors — one of the class of immunotherapy > used for non-small cell lung cancer
PD1/PDL-1 inhibitors > evade immune detection
By blocking this interaction > checkpoint inhnibitors will allow the T cells to recognise & attack cancer cell > enhance the body’s natural ability to fight the tumour
PDL-1 inhibitors > block PD1 receptor on T cells > stopping it from interacting with PDL-1 — ligand on tumour cell > this will reactivate the T cells > allowing them to recognise & attack cancer cells that will otherwise evade the detection
These inhibitors have become standard therapy for advanced non-small cell lung cancer, espeically in patients with high PDL-1 expression
Work by preventing PDL-1 ligand on tumour cells fromm binding to PD1 receptor on T cells
By blocking this interaction, PDL-1 inhibitors will enable T cells to stay active & continue targeting & destroying cancer cells
Used in patients with high PDL-1 expression
Can be used alone or in combination with chemotherapy
CDLA4 inhibitors — normally enhance T cell activation at the earliest stage in the immune response
Example — Epilipumab
→ Stimulates T cells to become more effective at targeting the cancer cell
Often used in combination with PD1 inhibitors, to boost the immune system & increase the chance of durable response
Immunotherapy for early stages NSCLC
Early stage > often do surgery first & then immunotherpay, or opposite
Immunotherapy is done as an additional treatment approach to either neoadjuvant (before surgery) or adjuvant (after surgery)
This is normally in combiantion with chemotherapy
Neoadjuvant immunotherapy — involves the administration of PD1/PDL-1 inhibitors — e.g. pembrolizumab or nivolumab — before surgery > to shrink down the tumour & making it more amenable to surgical resection
By reducing the tumour side before surgery > can potentially improve surgical outcomes & leadd to better long term survival
Adjuvant immunotherapy — after surgery
PD1/PDL-1 inhibitors can be used as adjuvant therapy > to prevent recurrence & can eradicate micrometastasis that may have spread during the early stages of cancer
This is crucial for reducing the risk of relapse, especially when it comes to high risk patients who may have more extensive disease or higher likelihood of cancer coming back
Benefit of combining immunotherapy with chemotherapy, either before or after surgery — will reduce the tumour size & make it easier to resect & prevent any recurrence of cancer after surgery by targeting any microscopic cancer cells that may still be remaining in body
Immunotherapy for late stages NSCLC
Late stage > won’t be able to do the surgery anymore > have already spread to other organs
Chemotherapy — first-line of treatment for stage 3 or 4 lung cancer
Mostly uses combination — chemotherapy with radiotherapy
Goal to shrink down tumour > to decrease symptoms & improve overall survival
PDL-1 inhibitors > will normally be used as adjuvant therapy > used in combination with chemotherapy for any lung cancer cases that can’t be performed by surgery
Examples — pembuluzimab, tenluzumab
Help to boost the immune system > enabling it to recognise & attack the cancer cells more effectively
Their use has shown to improve progression-free survival & overall survival, especially in patients who may not respond to conventional chemoradiotherapy alone
Benefit of combination — will be able to control the disease, reduce tumour size & improve survival outcome
Advanced stage 4 — has already spread to any distant organs — e.g. liver, bones & brain
→ Incurble
Treatment options will be focusing on extending survival & improving quality of life
Pembulizumab, nivolupimab & etisoluzumab > used as either monotherapy or in combiantion with chemotherapy > to target cancer cells & enahance immune response
In cases where the patients have a higher PDL-1 expression > then the monotherapy with PD1/PDL-1 inhibitors is effective > better response rate & survival
For combination therapy for patients with a lower PDL-1 expression, or non-responder s to monotherapy > combination therapy with chemotherapy or CTL4 inhibitors — e.g. ipilupumab — may be used > to boost immune activation & improve treatment efficacy
By combining chemotherapy with immunotherapy > enhance immubne system’s ability to attack the cancer while also directly shrinking the tumours through chemotherapy
Important for treatment of metastatic stage of non-small lung cancer & helping with quality of life
Personalised Therapy Based on Mutation Status
New Standards
Depending on the stage of lung cancer > use monotherapy or combination
Combination therapy — either immunotherapy + standard systemic chemotherapy; or 2 immunotherapies
Pembrolizumab + Platinum-based chemotherapy > used when the patient needs the checkpoint inhibitors to boost the immune system & allows to have a better target at attacking the cancer cells
The choice of combination therapy depends on the patient’s tumour type, PDL-1 expression & tumur mutation
Immunotherapy — Personalised Therapy: Side Effects
Study the whole website on eviQ
Immunotherapy, especially for checkpoint inhibitors, carry a risk by triggering immune related adverse events
These side effects happen becuase the immune system is being reactivated & starts attacking the normal healthy tissue in the body > leading to inflammation & damage
Pneumonitis — inflammation of the lungs — one of the most common adverse effects for patients with immunotherapy > symptoms are shortness of breath, cough & fever
Hypothyroidism — underactive thyroid > occurs when the immune system attacks the thyroid gland > leading to fatigue, weight gain & cold intolerance
Colitis — inflammation of colon > can cause diarrhoea, abnormal pain & intestinal perforation
Hepatitis — inflammation of liver > can cause elevated liver enzymes, jaundice & fatigue
Dermatitis — inflammation of skin > rash, itching or more severe skin reaction
Management — Cortcicosteroids & immunosuppressants
By suppressing the overactive immune system
Corticosteroids — 1st line treatment to reduce inflammation & control symptoms
The specific type of toxicity determines the choice & dose of immunosuppressive therapy
E.g. colitis may be managed with high dose steroids, while hepatitis may require corticosteroids with additional liver support therapies
Pseudoprogression — refers to tumurs may appear to grow on imaging studies, before they shrink as the immune system mounts an attack on the tumour
Molecular Targeted Therapy — EGFR Tyrosine Kinase Inhibitors (TKIs)
T79M mutation — common mutation that happens in EGFR domain, especially in patients who develop resistance after initial treatment with 1st & 2nd generation of EGFR
This mutation will alter ATP binding pocket of EGFR receptor & preventing EGFR inhibitors from effectively binding to receptor & inhibiting its activity
Because of that, a 3rd generation EGFR TK1 has been developed — oscimiumneb
Specifically designed to target T97M > providing solution for patients with resistant EGFR mutations
However, when it comes to 3rd generation resistance > it is called C797S mutation > developed during the treatment of osciminub
This mutation alters ATP binding site > leading to resistance to osciminub & blocking its ability to bind to EGFR receptor > leadint to a continuation of tumour growth despite therapy being used
EGFR amplification — occurs when cancer cells increase in number of copies of EGFR gene
This can lead to overexpression of EGFR protein > make EGFR TK1 less effective
This amplification of EGFR gene will increase the numebr of recpetors on cancer cell surface
It will also lead TKI drugs to compete with a higher number of receptors
→ Diminish the effectiveness of blocking the tumour growth
Upregulation of other EGFR family members > can restimulate tumour growth & overcome block induced by EGFR inhibitors
EGFR pathway bypass
Activation of other ….
These pathways are involved in promoting cell survival & growth > their activation allows cancer cells to continue to divide despite of EGFR blockade
Cells ….
Cross mutations are known to bypass EGFR signalling pathway > rendering EGFR targeted therapy ineffective
Histological tranformation
Some ….
These …..
This transformation may occur because of genertic alteration or epigenetic changes that reprogram the cancer cells into a more aggressive phenotype
Molecular Targetted Therapy — EGFR Tyrosine Kinase Inhibitors (TKIs)
EGFR mutation — major driver of non-small cell lung cancer
→ Leading to activation of ERK MAPK pathway …..
→ These mutations can cause EGFR receptor to become more constantly active & driving the tumour growth & metastasis
1st Gen — used if there is resistance developed
Molecular Targetted Therapy — EGFR Tyrosine Kinase Inhibitors (TKIs)
1st Gen EGFR — resistance develops quickly — within 9-14 months
2nd Gen EGFR — resistance develops, but not as quickly as for 1st Gen
Once the acquired resistance is happened > go to 3rd Gen
EGFR Acquired
EGFR > have a problem with resistance > major challenge for non-small cell lung cancer
Strategy > use combination therapy, with chemotherapy or targeted therapy to counter or bypass the mechanism > to allow the patient to stay on EGFR inhibitors for a bit longer
ALK-EML4 Translocations
Mutations in the chromosome
Chromosome shuffle > lead to tumour growth
ALK/EML4 genes are separated on chromosome 2
Important in non-small cell lung cancer
Because they swap places in genetic rearrangement
Creates ALK/ML4 fusion gene
Creates abnormal fusion protein
→ Oncogenetic driver
→ Drives uncontrolled cell growth
→ Contributed to tumour formation
→ Activates the signalling pathway that helps cancer cells to grow, survive & spread
Activates
RAS — promotes cell growth & survival
STAT — helps with cell proliferation & immune evasion
PI3K — encourages cancer cells to survive & evade surrounding tissues
These pathways are like highways for cancer cells > enabling them to grow & spread, while also avoiding being detected by immune system
This is why the tumour is more aggressive & difficult to treat
ALK-EML4 Translocations
Tyrosine ……. (TKI)
TKI — targeted therapy used for ALK positive non-small cell lung cancer
Inhibits abnormal ALK protein that is driving cancer cells to proliferate
Brigatanib — 2nd Gen TKI
Targets ALK gene & is effective in treating LAK positive tumour
Beneficial for patients who have developed resistance to 1st Gen ALK inhibitors & shownefficacy in patients with ALK positive non-small cell lung cancer, even for those with a brain metastasis
Provides progression-free survival & helps control disease progression
ADR — early pulmonary events — e.g. pneumonitits & interstitial lung disease
→ very severe & require careful monitoring of lung function during treatment
Alectinib — 2nd Gen multi-TK inhibitor > targets ALK, NTRK & RAS1
Expanding its therapeutic potential for patents with those mutations
Excellent efficacy in treating ELK positive, also especially for patients with brain metastasis > because they cross BBB
Because of that > side effects are muscle pain & fatigue > manageable
Lorlatinib
Useful for those who develop resisitance to 1st & 2nd Gen ALK inhibitors
Excellent activity against ELK positive tumours, including those that have developed resistance mutation or brain metastasis
Can cross BBB
→ one of the advantages
ADR — high incidence of neurological, cognitive & speech issues — e.g. memory loss, difficulty concentrating
Peripheral neuropathy — nerve damage causing tingling & numbness
ROS1 Gene Fusion in NSCLC
Activates …..
RAS-MEK-ERK — involved in cell proliferation & survival
JAK-STAT3 — plays a role in immune revasion & inflammation
PI3K-AKT-mTOR — regualtes the self-metabolism & growth
SHP2 — promotes cell survival & proliferation
These pathways allow ROS1 positive tumour to bypass normal growth control mechanism & making ROS1 inhibitors highly effective treatment option
First line
Entrectinib (effective in CNS disease)
Targets ROS1 fusion & has good penetration to BBB
→ Making it effective in treating any of the brain metastases & a common complication of advanced ROS1 positive
Crizotinib — multi-target TKI > targets ALK, MATS & ROS1
Many patients will develop resistance to this > need 2nd line therapy
Multi-TKI inhibitors
KRAS Mutations
KRAS Pathway Activation:
….. cycling between an inactive ….
Active state — KRAS will trigger downstream signalling pathway & promote cell growth & proliferation
BRAF Mutations
BRAF mutation — oncogenic > uncontrolled growth of cancer cells
Targeted Therapy:
BRAF
Dabrafenib (BRAF inhibitor)
Specifically targets & inhibits the mutant > blocking activation of MAC & ERK pathways > stopping tumour growth
Used in combination with trametinib (MEK inhibitor) > further blocks downstream signalling of MEC pathway
→ Increase treatment efficacy
→ Enhances it as 1st line treatment
→ Blocking both BRAF mutation & downstream of MEC signalling
Synergestic effect > improve patient outcome over monotherapy
Platinum
By blocking this chemotherapy agent > blocking DNA crosslink > no more DNA replication or transcription > cell death of both healthy & cancer cells
Non-specific chemotherapy > medications have side effects
Management of side effects — hydration, dose adjustment & neuropathy adjustment