What are 2 important mutations types of mutations that cause malignancies?
1. Oncogenes (accelerators)
2. Tumor suppressor genes (brakes)
26 y/o surfer discovers dark, irritated lesion on upper back that he ignores for one year. Eventually, due to bleeding, he has it examined. Biopsy yielded melanoma.
Unfortunately, he was found to have multiple lung lesions and biopsy also was positive. His tumor was found to be positive for the B-Raf V600 mutation. What targeted treatment would you use? Why?
- Vemurafenib: interrupts the B-Raf/MEK step in the B-Raf/MEK/ERK pathway if B-Raf has the common V600E mutation
1. 53% response and overall survival (OS) of 15.9 m in mutated tumors (50%) -> responses prolonged with concurrent MEK inhibition
- BRAF mutations tend to be from sunburns during youth
What is the most common inherited breast cancer tumor suppressor gene mutation?
62 y/o never smoker female presents with cough and shortness of breath. Chest X-ray demonstrates pleural effusion and mass in the right lung (shown here). Exam of the fluid demonstrates adenocarcinoma.
Impression: Metastatic lung cancer
Plan: Send cell block for mutational analysis; If negative, standard therapy includes chemotherapy with expected survival of 6-12 months and Moderate toxicity
She would be most likely to have a mutation amenable to targeted therapy if she was of what ethnic background? What mutation and tx?
- Lung adenocarcinoma (unlike small cell or squamous cell carcinoma) often arises in never smokers, esp. EAST ASIAN
- Mutation in EGFR (exons 19 and 21), which can be inhibited via Erlotinib (blocks tyrosine kinase activity intracellularly)
1. Activating mutations present in 5% smokers, 15% non-smokers, 50% never smokers with adeno-carcinoma
NOTE: Dr. Weir also mentioned HER2 mutation, ALK translocation, and KRAS mutation as potentially treatable causes of lung adenocarcinoma. All of these, incl EGFR, are aberrantly activated oncoproteins (oncogene addiction) in never-smokers
What is Everolimus?
- mTOR inhibitor often paired with Tamoxifen to treat breast cancer (derivative of Sirolimus) due to synergistic effect limiting cross-talk b/t estrogen receptor and mTOR (tyrosine kinase) pathways
What is Sunitinib? How is it related to the microscopic pathology shown here?
- Targeted therapy for the IC VEGF tyrosine kinase
1. 105 patients with progressive renal cancer
2. 44% partial response and 22% stable disease
3. Median duration of response 10 months
- Used to treat tumors that need angiogenesis, i.e., renal cell carcinoma, GIST, or hemangioblastoma
Explain what is going on here. What drug would be used to limit this pathway, and for which cancer?
- Sonic Hedgehog (SHH) Pathway: transmembrane Patch receptor a has leash on SMO, which drives tumor via GLI1 and GLI2 transcription factors, which move to nucleus
- Vismodegib: SMO antagonist in basal cell carcinoma
What syndrome is associated with an inherited TP53 mutation?
- LiFraumeni syndrome: rare autosomal dominant cancer predisposition hereditary disorder characterized by sarcomas, and cancers of breast, brain, and adrenals
What is Enzalutimide?
- Androgen receptor antagonist
1. Median survival improved from 13.6 to 18.4 months in castrate resistant prostate cancer
2. Castrate resistant: progressing with markedly suppressed testosterone levels (b/c even when you run out of testosterone, the cancer adapts to this)
- In Europe, typically treat w/castration -> no difference in outcomes, but big difference in $$$
40 year old African American female comes to you with fear of breast cancer. She has two sisters who developed breast cancer, one at 36 and one at 46. What tumor suppressor mutation is she most likely to have?
43 y/o mother of two found rapidly enlarging mass in her breast. Needle biopsy demonstrated adenocarcinoma of the breast that was estrogen and progesterone receptor negative and Her 2 neu positive. At the time of sx, four lymph nodes were found to contain breast cancer metastasis. Other staging tests found no additional spread of the cancer. What targeted therapy could you use in this case? Why?
- Trastuzumab: monoclonal Ab that binds to EC domain of HER2/neu receptor (a tyrosine kinase)
1. HER1 is an epidermal growth factor receptor, and HER2 acts on its own, or dimerizes with HER3
2. Very helpful treatment in metastatic cancers, esp. with Pertuzumab, which prevents dimerization
3. Also a Trastuzumab chemotherapy (T-DM1) that delivers chemo directly to breast cancer cells
67 y/o accountant is being followed for metastatic breast cancer to her bones (shown here). Tumor identified as both estrogen and progesterone receptor positive. What is a synergistic pair of targeted treatments you could use? Why?
- Tamoxifen: antagonist (competitive inhibitor) of estrogen receptor in breast tissue (behaves as an agonist in some other tissues, i.e., endometrium)
- Everolimus: mTOR inhibitor (derivative of Sirolimus)
- When Everolimus is added to Tamoxifen in hormone therapy failures in metastatic breast cancer, time to cancer progression improved from 4.5 to 8.6 months
1. Blocking mTOR inhibits cross-talk b/t estrogen receptors and tyrosine kinase pathway via non-genomic ER-mediated response
What is Trastuzumab?
- Monoclonal Ab HER2/neu receptor antagonist
1. 34% improvement in overall survival in adjuvant setting for HER2+ breast cancer
What are the 4 main goals of treatment?
1. Cure disease
2. Extend life
3. Better QOL
4. Prevent impending disaster
What syndrome is caused by an inherited PTEN mutation? Which pathway is this in?
- Cowden syndrome (part of PTEN harmartoma syndrome): associated w/risk of benign and cancerous tumors of breast, thyroid, endometrium (uterus), colorectal, kidney, and skin (melanoma)
- P13K/AKT/MAPK pathway
Is C-kit an oncogene or a TSG?
78 y/o retired farmer presents to office with bone pain. His prostate is large and hard. His PSA is 223 (normal = 4). Bone scan reveals widespread metastases. Needle biopsy of prostate diagnoses adenocarcinoma.
He is started on anti-hormonal therapy. His disease is well controlled with a good quality of life for three years. Then he begins to hurt more and his bone scan shows new metastases. What combined therapy would you use to treat this? Explain your answer.
- Enzalutamide and an LHRH antagonist (or agonist)
- Enzalutamide is an androgen receptor antagonist that prevents migration of transcription factors to the nucleus
- LHRH is released by the hypothalamus, turns on leutinizing hormone in the pituitary, and then testosterone in the testicle -> antagonist limits LHRH, and agonist overdrives hormone in the pituitary, turning the cycle off
- NOTE: most prostate cancers are hormone-driven, so if you block these, you can control the cancer for years
Name a common mutation that can lead to malignancies in a small % of lung cancers.
EGFR and ALK
What is Crizotinib?
- EML4-ALK mutation
- About 5% lung cancers (usually adenocarcinoma)
- Increased in never smokers, Asian, female
- 57% response, and 72% progression free in 6 months
Are targeted treatments in genomic medicine curative? Why or why not?
- When one pathway is targeted to suppress a cancer, mutations may develop that allow cancer to progress around the therapy
1. Also, other pathways within the cell may increase in activity to bypass the therapeutic effect.
What percentage of women with BRCA 1/2 mutations develop breast cancer by age 70? In which populations are these mutations most frequent?
- BRCA 1: Ashkenazi Jews
- BRCA 2: AA
In advanced cancers, do you want to use least, or most, toxic treatment first?
66 y/o M followed for iron deficiency anemia, presented with gross hematuria and was found to have a large mass in his kidney. It was removed by urology. One year later, multiple lung lesions developed. What did biopsy demonstrate? How would you have treated this if it had been caught earlier?
- Renal cell carcinoma, which requires VEGF (assoc w/ VHL mutation in germline or cancer itself)
- Sunitinib is drug of choice: IC inhibitor of VEGF receptor
- Von Hippel-Lindau disease: mutation in the VHL tumor suppressor gene (on 3p chrom) -> loss of VHL protein activity results in increased HIF-1, and consequently, increased VEGF and PDGF angiogenic factors
1. Can lead to tumors needing VEGF: renal cell carcinoma, pheochromocytoma (adrenal gland tumor), hemangioblastomas (CNS tumors, i.e., spinal cord, brain stem), pancreatic cysts, etc.
- Soft tissue metastases in lower chest and flank after nephrectomy
79 y.o homeless man seen in the ER with a large tumor anterior to his left ear. Evaluation demonstrated that it was a basal cell skin cancer that invaded the bridge of his nose. Resection was attempted but positive margins were left behind. He was treated with radiation to clean up the margins and was lost to follow-up. 8 months later he was again seen in the emergency room with severe facial pain and recurrent tumor. What targeted treatment would you recommend for this type of cancer? Why?
- Vismodegib: competitive antagonist of SMO receptor, part of the hedgehog signaling pathway. SMO inhibition causes transcription factors GLI1 and GLI2 to remain inactive, preventing expression of tumor mediating genes in the hedgehog pathway. Pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.
1. 43% response in locally advanced basal cell skin cancers w/medianresponse duration of 7.6 months
Name a cancer accelerated by a mutated c-kit oncogene.
Gastrointestinal stromal tumor
What is Tamoxifen? How is it different than aromatase inhibitors?
- Estrogen receptor antagonist in breast (and agonist in some other tissues, i.e., endometrium of uterus)
1. 50% response rate and >12 month median response duration in estrogen receptor (+) women with metastatic breast cancer
2. 20-30% reduction in breast cancer recurrence when used in an adjuvant setting (all known disease resected with known risk for recurrence)
- Aromatase inhibitors: don't block the estrogen receptor, but inhibit estrogen syn (work well in post-menopausal women only b/c younger women's bodies oversaturate to overhaul this antagonism)
What two types of cancer are associated with an inherited Rb mutation?
Retinoblastoma and osteosarcoma
58 y/o male smoker presents with mass in right neck. Throat exam reveals tonsil mass. Needle biopsy confirms squamous cell carcinoma of tonsil. Pt treated with chemotherapy and radiation until all disease gone, but comes to ER confused and with bone pain 1 year later. Found to have elevated serum Ca2+ and bone metastases. Cancer controlled by chemo for 6 mos, then progresses. What is the most common cause of this type of cancer? What are you going to do now?
- Common cancer in smokers, but most common cause of oropharyngeal cancer now HPV ( esp. as smoking incidence has gone down; obviously, this would not be true in pt. population with lots of smokers)
- Cetuximab: EC EGFR tyrosine kinase inhibitor(works very well in many head and neck cancers)
1. Median survival: 7.4m vs. 10.1m (b/c median, some people live much longer, and some much shorter)
What is the drug used to inhibit the central pathway shown here? Name the associated cancer described in class.
- Ematinib: inhibits the tyrosine kinase activity of C-kit
- GI stromal tumor
A 60 year old man presents with decreased appetite, early satiety, and need to expand his belt. See the attached imaging. What is going on? Name the pathway, ligand, and drug.
- GI stromal tumor (GIST): silent tumor in the abdomen, typically in the stomach
- Pathway: C-kit
- Ligand: Stem cell factor (Scf)
- Drug: Ematinib (limits the action of the C-kit tyrosine kinase, upstream of the RAS and P13K pathways)
1. GIST tumors are very sensitive to this tx, and may disappear in days b/c you are "turning off" the tumor
Can one mutation allow cells to overcome the body's boundaries for cell growth?
Usually, NO -> multiple mutations required to allow cells to overcome the body’s boundaries for cell growth
What is Erlotinib?
- PFS 9.7m vs. 5.2m compared to chemotherapy (routine practice to do test and use drug if applicable)
- Exons 19 and 21
- Higher in East Asian population
- Blocks tyrosine kinase activity of EGFR on the inside of the cell (Cetuximab would block EGFR activity outside of cell, but is used for treating colorectal or head and neck cancers)
72 y/o retired physician devo headache and weakness in left leg. X-rays reveal necrotic tumor in right brain. Tumor resected and patient treated w/radiation & chemotherapy. One year later the tumor begins to grow and pt becomes confused. What is going on here? What treatment would you administer?
- Recurrent glioblastoma is most likely to respond to Bevacizumab because these tumors tend to be highly dependent on angiogenesis
- Bevacizumab is a VEGF tyrosine kinase inhibitor that binds to the VEGF-A ligand EC, sequestering it, and preventing VEGFR-2 activation (and subsequent RAS and P13K pathways)
- NOTE: these therapies are very expensive. While this is the standard drug in second-line therapy, it doesn't really help you live much longer, but rather relieves tumor side effects (i.e., loss of speech)
Briefly describe how genomic medicine works.
For what cancers have these types of treatments been developed? There are 9 -> list the treatments and pathways too.
- With genomic medicine, we can identify mutation sites for many cancers and treat specifically the problem with targeted therapy
- Effective medicines against specific targets have been developed for (among many others):
1. Brain tumors: Bevacizumab (VEGF-A, EC)
2. Head and neck (and colorectal) cancer: Cetuximab (EGFR tyrosine kinase, EC)
3. Lung adenocarcinome: Erlotinib (EGFR), and Crizotinib (EML4-ALK)
4. Breast cancer: Erlotinib (EGFR tyrosine kinase, IC), Tamoxifen (estrogen receptor antagonism), Everolimus (mTOR inhibitor that can be combined with TAM), Trastuzumab (Her-2)
5. GIST: Imatinib (C-kit)
6. Renal cell carcinoma: Sunitinib (VEGF, PDGF)
7. Prostate cancers: Enzalutimide (androgen receptor blocker), leutinizing hormone blockers
8. Chronic leukemias: Imatinib (BCR-ABL tyrosine kinase)
9. Skin cancers: Vemurafenib (BRAF V600E/K) for melanoma, Vismodegib (SSH) for basal cell carcinoma