Sweatman - Lung Cancer Rx Flashcards
Why is the division between NSCLC and SCLC no longer used?
- Histologic subtype of NSCLC now has to be reported due to advent of targeted therapy
- EGFR mutations are extremely rare in large cell, small cell, and pure squamous carcinomas
1. Evident in significant # of adenocarcinomas - Bevacizumab associated w/high risk of bleeding in squamous lung cancers -> only approved for use in non-squamous NSCLC
About what % of NSCLC are squamous vs. adenocarcinoma?
- 50% adenocarcinoma
- 30% squamous
How does the EGF receptor work? How does it “malfunction?”
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Normal cell (A): ligand-induced receptor activation leads to receptor dimerization and trans-phosphorylation of 2 tyrosine residues
1. Transduced to nucleus via signalling, and nuclear transcription can lead to cell growth, proliferation, and avoidance of apoptosis -
Cancer cells (B): proliferative pathway gains func via 1) receptor amplification, 2) mutation, or 3) trans-location
1. Chromosome rearrangement can lead to: the transcriptional activation of proto-oncogenes or creation of fusion genes encoding chimeric proteins w/transforming properties
How do TKI’s INH EGFR? What are the 4 NSCLC resistance mechs?
- TKI INH the phosphorylation step, and absence of proliferative signal leads to apoptosis -> this should lead to a clinical anti-tumor response
- Resistance mechs (see attached image):
C. Drug binding site (T790M) mutation
D. Amplified MET (hepatocyte growth factor receptor, HGFR) phosphorylates ERBB3 (circumventing drug presence)
E. HGF activates P13K/Akt via MET, independent of ERBB3 and EGFR
What is an anti-apoptotic IC mech of resistance to TKI’s?
- Polymorphisms in apoptosis genes: downstream of EGFR
1. Example: BIM polymorphism -> absence of pro-apoptotic BH3 domain in 15% of East Asians (predictive of significantly shorter survival than patients with “normal” BIM)
What is a pro-proliferative IC mech of resistance to TKI’s?
- KRAS and BRAF muts can render anti-EGFR drugs (Mab’s or TKI’s) ineffective due to proliferative path constitutively active DOWNSTREAM of drug-induced blockade
- Genotyping for mutation can be a deciding factor NOT to treat with Mab, e.g., Cetuximab
What is the EML4-ALK translocation?
- Family of abnormal (pro-malignant) fusion genes
1. Echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes
2. Activates the MEK/ERK pathway and cell proliferation (drug for it now) - 2-7% of NSCLC -> more prevalent in non-smokers, pts w/hx of light smoking, & pts w/adenocarcinomas
Why can blocking VEGF be helpful? Problematic?
- Proliferating tumors need blood supply, which is maintained by cells sensing oxygenation via HIF-1, and the release of VEGF
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Potential downsides:
1. Reduce distribution of concurrent chemo
2. Induce proliferation of more aggressive cells (green in image) that have capacity to spread to other organs
Why is human variation so critical when it comes to anti-cancer drugs, like TKI’s?
- Metabolism may be influenced by several host factors, including bioavailability and host pharmaco-genetics
- Variation in the germline constitution of individual patients can have significant impact on response to tx and degree of toxicity
- By inhibiting their target kinases, these agents extinguish crucial downstream signalling pathways involved in normal cell growth
- Host tissues can also influence efficacy of kinase inhibitors by secreting factors, e.g., HGF, in a paracrine fashion
Which mutations are more common in non-smokers?
- EGFR (45%)
- EML4-ALK
- HER2
- hMSH2 (40%)
- Not only smokers get lung cancer
Why is genetic testing of adenocarcinomas so important?
- Actionable mutation in 60% of patients
- Data used to either:
1. Treat according to guidelines based on EGFR results (KRAS and ALK too)
2. Offer enrollment in clinical trials targeting other ID’d mutations (BRAF, MET)
What are the existing genetic testing guidelines?
- Routine testing recommended for EGFR muts and ALK rearrangements in ALL ADENOCARCINOMAS
1. Not recommended in pure squamous cell tumors due to very low diagnostic yield - DNA sequencing is the method used in most EGFR studies -> discordance of up to 28% b/t 1o tumors and distant metastases
- Fluorescence in situ hybridization (FISH) preferred and FDA-approved choice for ALK gene rearrangement testin
What is the current recommendation for preventive scans for smokers?
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Smokers (55-80 y/o) with >30-pack history and those who have quit in the last 15 years should get low-dose CT scans of lungs to look for possible tumors
1. 2 previous reviews found insufficient evidence to support annual screenings - Small risk of radiation exposure from low-dose scans outweighed by benefits of detecting abnormal growths early and intervening w/tx
What are the standard tx plans for SCLC and NSCLC?
- SCLC: metastasis early, so radiation/chemo the only option
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NSCLC: sx resection if no metastasis (early stage)
1. Chemo/radiation used in adjuvant, neo-adjuvant or maintenance role to:
a) reduce bulk of the tumor (facilitating sx) and eradicate early micrometastases OR
b) prevent growth or metastasis
2. Pre-op chemo may delay potentially curative sx -> metastasize very early, most commonly spreading to adrenals, liver, brain, and bone
What are the standard tx options for SCLC?
- Etoposide + Cisplatin or Carboplatin
OR
- Cisplatin + Irinotecan
- Cisplatin + Etoposide + Ifosfamide
- Cyclophosphamide + Doxorubicin + Etoposide
- ”” + Vincristine
- Cyclo + Doxo + Vincristine
- Cyclo + Etoposide + Vincristine
What are the standard tx options for NSCLC?
- Cisplatin AND Paclitaxel, Gemcitabine, Docetaxel, Vinorelbine, Irinotecan, or Pemetrexed (commonly a taxane)
- Pemetrexed maintenance: for pts w/stable or responding disease after 4 cycles of nonpemetrexed-platinum combo therapy)
- Based on appropriate genetic markers, TKI’s and VEGF inhibitors may also be used:
1. EGFR TKI’s for pts w/EGFR+ genetic test
2. Bevacizumab (pts w/non-squamous histo, no brain metastases, and no hemoptysis)
3. Erlotinib: first-line tx for locally advanced or metastatic NSCLC after failure of at least 1 prior chemo regimen, or for maintenance tx of “” that has not progressed after 4 cycles of platinum-based first-line chemo
What is the MOA for Cisplatin and Carboplatin?
Form DNA intrastrand crosslinks and adducts
What is the MOA for Cyclophosphamide?
Pro-drug of active alkylating moiety
What is the MOA for Docetaxel?
Microtubule stabilizer inhibiting depolymerization
What is the MOA for Doxorubicin?
Intercalator, free radical generator, topo II INH
What is the MOA for Etoposide/VP-16?
DNA-topo II complex stabilizer
What is the MOA for Gemcitabine?
DNA polymerase inhibitor via incorporation of triphosphate form during DNA synthesis
What are some of the (un)common TKI side effects?
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Common:
1. EGFR: diarrhea, N/V, dermatologic, elevated hepatic enzymes, opthalmic (except Afatinib)
1. ALK: constipation, diarrhea, N/V -
Uncommon:
1. Gefitinib - renal
2. Ceritinib - fatigue, DEC hemoglobin, hyperglycemia (but no opthalmic, unlike Crizotinib)
What do you see here?
- EGFR-induced rash: common and potentially severe AE
- May necessitate specific txs with steroids, antimicrobials, and oatmeal lotions
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What should you do if your lung cancer pt on TKI’s presents with a rash?
What 2 things do these graphs tell you?
- Erlotinib produces a significant survival effect, especially in the short-term
- This effect is dependent on the molecular target, in this case, EGFR overexpression by the tumor
What is the theoretical resistance mutation to Crizotinib?
- G2032R ROS1: has been shown to reduce drug activity in in vitro kinase activity assays
- Emergence of resistance most likely reflects an outgrowth of pre-existing tumor clones with inherent resistance at this site
How does clinical staging of lung cancer affect genetic testing?
