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A 67-year-old patient with a less than 15 pack-year history of tobacco use, presents with headache, ataxia, gradually worsening back pain and cough. There is a diagnostic evaluation including imaging, which reveals brain and bone metastases, mediastinal adenopathy and a right lower-lobe lung mass suspicious for a lung primary.  Pathologic examination of the bone metastasis and a bronchoscopic sample from the right lower lobe lung mass is consistent with metastatic non-small cell lung adenocarcinoma (CK7, TTF1, and napsin A positive; CK20, p40 negative). The right lower-lobe lung sample has high tumor cellularity, whereas the bone metastasis has low cellularity. According to AJCC 8th edition criteria, the patient is diagnosed with stage IVA (T3N2M1c) adenocarcinoma of the lung.

Palliative systemic therapy is planned. To facilitate optimal selection of an evidence-based therapy, the medical oncologist requests tumor molecular profiling.

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You are considering genetic testing to aid in selecting chemotherapy.

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What sample would you send for testing?  Explain your answer in up to two sentences.

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There are 2 gene panels you are considering for your patient (workshop faculty do not endorse any specific laboratory):

Laboratory 1: https://bit.ly/TRIGLab1

Laboratory 2: https://bit.ly/TRIGLab2

Which panel would you select?  Explain your choice in up to three sentences. Review relevant guidelines.

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Would you order molecular testing if this patient had been diagnosed with stage 2 lung adenocarcinoma with a complete resection of the tumor?  Why or why not?

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The patient is found to have an EGFR exon 19 deletion and is started on treatment with erlotinib.  Initial scans indicate treatment response.  After 16 months, however, the patient develops new symptoms and a CT scan shows progression of the disease with a new liver lesion.   Molecular testing shows a new EGFR variant T790M, which confers resistance to the initially prescribed tyrosine kinase inhibitor.

The patient is started on osimertinib and has stable disease until a year later, when a CT scan shows significant enlargement of the initial liver lesion and new metastatic liver foci.

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Options for sampling include a liver metastasis and a liquid biopsy. Which would you select for subsequent molecular testing, and what are the advantages and disadvantages of each?

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A liquid biopsy is sent and you receive the report at http://bit.ly/liquidbiopsyreport.  Using CIViC (https://civicdb.org/), and OncoKB (https://oncokb.org/), what is the clinical significance of the EGFR C797S and PIK3CA E545K variants, based upon what evidence?

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Based on this information, what treatment options may be available for this patient? Is there a biological relationship between EGFR and PIK3CA that may guide your decision?

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The patient is a 55-year-old woman with a 70 pack-year history of smoking diagnosed with metastatic lung adenocarcinoma who has failed several lines of therapy.  A sample is sent for a next-generation sequencing (NGS) panel testing for variants in 324 genes.

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How might your discussion with the patient regarding testing using this large gene panel be different than if you ordered single gene testing for EGFR?

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You receive the molecular testing report at http://bit.ly/moleculartestingreport and note an STK11 Q170* variant ((STK11):c.508C>T (p.Gln170Ter)). Using ClinGen (https://www.clinicalgenome.org/).

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What is the function of the STK11 gene?  Is there an association with any familial cancer syndromes?

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What is the reported clinical significance and based on what evidence?

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Does the molecular testing report recommend any additional follow-up for patients with this variant?

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What are other diseases in the differential diagnosis of Peutz-Jeghers Syndrome? (Hint: Through the STK11 ClinGen entry, use GeneReviews and look at table 3 in the article).

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List two laboratories in the United States that offer testing for variants in this gene. (Hint: Through the STK11 ClinGen entry, use GTR)

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In looking at the testing report, you note that on the first page of the appendix there is a list of “Variants of Unknown Significance."

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Using ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), what is the reported clinical significance of the BRCA2 p.H2074N variant and based on what evidence?

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Using PolyPhen (http://genetics.bwh.harvard.edu/pph2/), what is the predicted effect of the BRCA2 p.H2074N variant on protein structure?

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Would you have put the BRCA2 p.H2074N in the genomic testing report?  Why or why not?

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Regarding the STK11 and BRCA2 variants, would you discuss the results with the patient?  Would you proceed with any additional testing or referrals?  What other information would be helpful in determining how best to proceed?

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You notice your patient has a BRAF variant in addition to an STK11 variant.  You are wondering how many other patients have variants in both these genes.

(HINT: Go to the cBioPortal homepage (http://www.cbioportal.org/):
1.) On the left, under “Select Studies for Visualization and Analysis,” click on Lung and then, scroll down on the right and click on Lung Adenocarcinoma to select those studies
2.) Click on “Query by Gene”
3.) Select Molecular Profiles and only click Mutation
4.) Scroll down to Enter Genes and in the box that says Enter HUGO Gene Symbols, enter BRAF and STK11 on separate lines
5.) Click Submit Query)

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Using the Mutual Exclusivity tab, what is the frequency of lung cancer specimens that contain both BRAF and STK11 variants?

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Using the Oncoprint tab, scroll across the colored bars and select a  patient that has both an STK11 truncating variant and a missense BRAF variant (like your patient). What information is provided?

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Using the Mutations tab, how many patients have an STK11 Q170* variant?  What information is given regarding “annotation?”

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