IE 2: Lung Cancer

What is the leading cause of cancer deaths in male and females?

• Lungs and bronchus

Why do males have a faster declining death rate than females?

• Cigarette smoking cessation education

• Difference in historical pattern in smoking cessation

• Lung cancer related deaths among females increased in 2025 vs 2024

Why do Asian American women have increased lung cancer risk?

• Lung cancer pt death increase → big increase in asian American female non-smokers (40s and 50s)

• Possible risk factors (still need more studies)

  • Oncogenic mutations → most involving EGFR

  • Family hx of lung cancer

  • Hx of lung disease → tuberculosis and COPD

  • Exposure to cooking fumes and second hand smoke

  • Various putative risk factors

• EDUCATE ON RISK AWARENESS → this matters bc 5 year survival rates are single digit in late stages

What are the lung cancer classifications?

• Small cell lung cancer → 10-15%

• Non small cell lung cancer → 80% OF LUNG CANCERS DIAGNOSED IN THE US

  • Subtypes:

    • Adenocarcinoma (most common)

      • Glands in alveoli and slow growing

    • Squamous cell carcinoma

      • Bronchus

    • Large cell carcinoma (least common)

      • Fast growing and large cells in lung

    • Other

What is SCLC vs NSCLC?

• Small Cell Lung Cancer

  • Very aggressive and rapidly growing

  • A majority of patients (60-70%) initially present with disseminated disease outside the hemithorax (already spread)

  • Has a greater propensity for metastasis to lymph nodes and distant organs

  • Does not contain EGFR or EML4-ALK mutations (not tested)

• Non small cell lung cancer

  • Slower growth rate and doubling time than SCLC

  • Has a better overall prognosis (especially adenocarcinomas)

  • Classified and treated by subtypes

  • Surgery is more commonly used

  • Contains EGFR mutations

Why is the survival rate for lung cancer so low?

• Majority of cases are diagnosed at a later stage

What is known about lung cancer survival?

• 5 year survival rate = 22% overall

• Survival rates in early stage is better prognosis vs late stage (Make sure to screen) → waiting late stage causes poor prognosis

  • Survival decreases the farther the cancer spread

• MOST CASES ARE DIAGNOSED AT LATER STAGE

Why are many lung cancers diagnosed late?

• Sx do not usually occur until cancer is advanced (bc many early stages have no sx)

• Presence and severity of sx based on location and extent of tumor

  • **This is why screening hella important

What are leading risk factors of lung cancer?

• Cigarette smoking (20+ pack-years) → Causes 80% of lung cancer deaths in the US

  • Tobacco smoke contains many carcinogens (i.e. PAH)

  • Risk increases with both quantity and duration of smoking

  • Currently smoke or have quit within the past 15 years

  • Cigar and pipe smoking also increase the risk

  • A pack-year is equal to smoking 1 pack (or about 20 cigarettes) per day for a year.

    • A person could have a 20 pack-year history by smoking 1 pack a day for 20 years, or by smoking 2 packs a day for 10 years.

      • Multiply packs by years

• Exposure to secondhand smoke

• Of non-smokers between the ages of 40 and 79, women are at a higher risk of developing lung cancer than men

• Although cigarette smoking rates have declined in the US, developing countries are now seeing an increase in smoking rates

What are some environmental lung cancer risk factors?

• Exposure to radon gas – 2nd leading cause

  • Released from soil and can accumulate in indoor air

• Asbestos (particularly among smokers)

• Certain metals (chromium, cadmium, arsenic) and organic chemicals

• Radiation

• Air pollution

• Diesel exhaust

• Certain occupational exposures: rubber manufacturing, paving, roofing, painting, and chimney sweeping

What are genetic lung cancer risk factors?

• Familial history of lung cancer

  • Especially in non-smoker parents or siblings

• Germline mutation

  • EGFR T790M mutation (???): more study warranted.

• Somatic mutations:

  • Tumor suppressor gene (i.e. p53)

  • BCL-2 overexpression

  • EGFR mutation

  • KRAS gene mutation

  • ALK (anaplastic lymphoma kinase) rearrangement

  • Others driver gene mutations (i.e. ROS1, NTRK, MET)

What are PMH lung cancer risk factors?

• COPD

• Pulmonary fibrosis

• *Asthma is not a validated risk factor for lung cancer

What can you do for lung cancer prevention and early detection?

• Smoking cessation and avoidance of implicated environmental
  exposures

• No evidence-proven chemoprevention agents yet

• No tumor biomarker to detect lung cancer at early stage

• Early detection based on imaging screening recommendations from the American Cancer Society (ACS) (2023) and U.S. Preventative Services Task Force

  • Low-dose computed tomography (LDCT) reduces lung cancer mortality by 20% compared to standard chest x ray in high-risk individuals

    • National Lung Screening Trial

• U.S. Preventive Services Task Force

  • Recommend annual screening for lung cancer with low-dose computed tomography in asymptomatic individuals aged 50 to 80 years who have a ≥20 pack-year smoking history and currently smoke or stopped smoking within the past 15 years.

  • Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

What is the national lung screening trial?

• Annual screening by LDCT or chest x-ray

• NLST reported 20% fewer lung cancer deaths in those screened with LDCT vs chest x-rays (bc LDCT can see early stages)

What is the NCCN lung cancer screening recommendations?

• High risk → Age 50 or more and 20 or more pack year hx of smoking → annual low dose CT

• Low risk → Age less than 50 and/or less than 20 pack yr smoking NO rec

• ** US preventive services task force → Age 50-80 and 20 pack year or more smoking hx and currently smoke/have quit within past 15 yrs → annual low dose CT

Before undergoing lung cancer screening, individuals should do what? (FYI kind of)

• Receive evidence-based smoking- cessation counseling and offered interventions if they currently smoke; and

• Engage in a shared decision-making discussion with a health professional about the benefits, limitations, and harms of lung cancer screening.

  • Screening test

  • Eligibility criteria

  • Benefits of screening

  • Health status may preclude screening benefits

  • Harms and limitations of screening

  • How often should to get screened

  • Importance of smoking cessation: Screening is not a substitute

What is the lung cancer diagnosis?

• Imaging (only tells if you have lung cancer not specific mutations)

  • Chest xray

  • Ct scan

  • ^^THESE 2 are anatomical imaging

  • Positron emission tomography (PET) scan → functional imaging (usual together with CT for better image)

• Biopsy - varies based on location of entry into the lung (GOLDEN STANDARD)

  • Can tell you what mutation the pt is carrying

What is the SCLC staging and progonsiis?

• Insert pic

What are general principles of SCLC tx?

• CHEMO is essential in all stages of SCLC (BACKBONE is platinum)

  • Many single and combo regiments

• Radiotherapy very effective in limited stages but can also be used for extensive stage disease for palliation

  • Can use in combo with chemo

• Surgery has limited role

What is NCCN primary/adjuant systemic therapy in SCLC?

• Limited stage

  • Etoposide + Cisplatin (EP stands for Etoposide and Platinum)

  • EP plus radiation in limited disease

• Extensive stage

  • Carboplatin + Etoposide + Ateolizumab (anti-PD-L1)

  • Carboplatin + Etoposide + Durvalumab (immune checkpoint regulators aka anti-PD-L-1 drugs)

  • New tx: Tarlatamab

• NO DOSING OR FREQUENCY NEEDED (just class and drug)

What is Tarlatamab?

• The first and only DLL3-targeting Bispecific T-cell Engager therapy that activates the patient's own T cells to attack DLL3-expressing tumor cells.

• Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in Small cell lung cancer (SCLC) and other neuroendocrine tumors but minimally expressed in normal tissues.

• Its a matchmaker that pulls CD3 on T cells to the DLL3 in tumors together to allow T cells to kill cancer cells

  
  

What is NSCLC staging?

• AJCC “TNM” staging system

  • T = tumor → size and extent of main tumor

    • T1, T2, T3 (T3 is biggest)

  • N = Lymph nodes → degree of spread to nearby lymph nodes (if positive)

  • M = metastasis → degree of spread to distant sites

    • If found in liver

• Examples: T1, N0, M0 = early stage BUT T3, N3, M1 is bad late stage

What are the different NSCLC stages and survival rates?

• Stage 1 → only in lungs but no spread to lymph node

  • 5 yr survival rate = 58-73%

• Stage 2 → Cancer in lung and near lymph nodes

  • 5 yr survival rate = 36-46%

• Stage 3 → 3a cancer spread to lymph on same side of chest where cancer started 24% rate; 3b cancer spread to lymph nodes on opposite side of chest or above collar bone 3-7% rate

• Stage 4 → cancer spread to both lungs, to fluid in area around lungs or to other organs and part of the body

  • 5 yr survival rate <1%

In NSCLC tx, what are the operable stages (curable) and which are inoperable?

• Stage 1, II, IIIA operable

• Stage IIIA (high risk)/IIIB and IV are inoperable

• Systemic therapy following surgical resection

  • Chemo

    • Stage IB, II, IIIA → adjuvant cisplatin based (sequential meaning after surgery there is chemo)

    • Stage IIIA (high risk)/IIIB and IV → concurrent chemoradiation (chemo and radiation same time)

  • Immunotherapy

    • For pts with no known EGFR mutation or ALK rearrangement → Durvalumab, Atezolizumab, Pembrolizumab, Nivolumab

  • Targeted therapy

    • Osimertinib for EGFR mutation

    • Alectinib for ALK rearrangement

• Radiation alone

  • Stage 1 and II

What is known about findings at surgery? (FYI)

• Margin negative means surgeon did great job and took all tumor out → theoretically cured

• Margin positive = RESIDUE so the surgeon cannot remove all cancer cells

  • We can either do re-resection (preferred) or radiation therapy to reduce residue

What are initial and adjuvant tx for NSCLC?

• Insert pic

Reminder, when using adjuvant chemo in stages 1-3 what is the backbone?

• PLATINUM CHEMOTHERAPY

What are the driving mutations in NSCLC adenocarcinomas?

• KRAS mutation → 10-30%

• EGFR mutation → 10-15%

• ALK rearrangement → 4-8%

• **ONLY NSCLC can have mutations

What did the FLEX study show?

• Cetuximab showed good survival advantages over chemo alone

KRAS point mutation is what?

• G-protein with intrinsic GTPase activity and activating mutations results in unregulated signaling through the MAP/ERK pathway

• Most commonly seen at codon 12

• Presence of a KRAS mutation is prognostic of poor survival

• Owing to the low probability of overlapping targetable alterations, the presence of a known activating mutation in KRAS identifies patients who are unlikely to benefit from further molecular testing

  • NO OVERLAPPING MUTATION NEVER 2 MUTATIONS

What is known about EGFR gene mutations?

• EGFR is a receptor tyrosine kinase normally found on the surface of epithelial cells and is often overexpressed in a variety of human malignancies

• The most commonly described mutations in EGFR (exon 19 deletions, p.L858R point mutation in exon 21) are associated with responsiveness to oral EGFR TKI therapy; tumors that do not harbor a sensitizing EGFR mutation should not be treated with EGFR TKI in any line of therapy

• EGFR p.T790M (GERMLINE MUTATION)

  • Identification of germline EGFR p.T790M confers a high risk for lung cancer regardless of smoking status.

  • Most commonly observed as a mutation that arises in response to and as a mechanism of resistance to first- and second-generation EGFR TKI. n patients with progression on first- or second-generation TKI with p.T790M as the prima y mechanism of resistance, third-generation TKIs are typically efficacious

For KRAS mutations, what is first line?

• PD-1 inhibitor and if still progression then

  • Adagrasib or Sotorasib

For EGFR mutations what is first line?

• Osimertinib (preferred)

• Other rec: Amivantamab (Bispecific antibody to EGFR and MET) + Lazertinib

In ALK rearragement, what is first line?

• “A big elephant loves or ABLE”

  • Alectinib

  • Brigatinib

  • Ensartinib

  • Loriatinib