Thread by @benweinbergmd

@TumorBoardTues #TumorBoardTuesday 1/9📣
68 year old man p/w lower GI bleed requiring 7 units pRBCs, found to have cecal adenoca + 2 liver metastases (1.6 cm and 0.7 cm), subcm lung nodules
➡️right hemicolectomy and liver biopsy: pT3pN1b(3/27)pM1b, stage IVB disease, MSS, KRAS MT, what next?

@TumorBoardTues #TumorBoardTuesday 2/9
Patient recovers ➡️ FOLFOX c/b esophageal spasm vs. coronary vasospasm (no EKG changes but RBBB at baseline), occurs despite omitting oxaliplatin (unable to tolerate infusional 5-FU), stopped after 4 cycles
Given 1 dose of iri c/b C diff colitis, CT: SD

@TumorBoardTues Complete disclosure: this CT was stable, but some of the lung nodules were slightly smaller, indicating
they could be real

@TumorBoardTues #TumorBoardTuesday 3/9
➡️left liver lobectomy and wedge seg 8, 4 foci of metastatic disease removed ➖margins, CT now with slight growth of lung nodules.
➡️ very low dose capecitabine (500 mg daily) and titrated up, lung lesions grow
➡️ RLLobectomy: ➕metastatic disease

@TumorBoardTues #TumorBoardTuesday 4/9
NGS on the lung resection path reveals KRAS G12D, MSS, low TMB (6), PD-L1 negative, 2 mutations in APC, a TP53 mutation, ERBB2 non-amplified, and a POMK-NRG1 fusion…

What’s an NRG1 fusion???

@TumorBoardTues #TumorBoardTuesday 5/9
NRG1 fusions create a ligand for the ERBB3 receptor, inducing heterodimerization with ERBB2 and downstream activation of PI3K-AKT and MAPK pathways

Fernandez-Cuesta and Thomas. Clinical Cancer Research 2015. @CCR_AACR
clincancerres.aacrjournals.org/content/21/9/1…

@TumorBoardTues @CCR_AACR #TumorBoardTuesday 6/9
NRG1 fusions are seen at low frequency across malignancies:

Jonna et al. Clinical Cancer Research 2019. @SushmaJonna @StephenVLiu @CCR_AACR clincancerres.aacrjournals.org/content/25/16/…

@TumorBoardTues @CCR_AACR @SushmaJonna @StephenVLiu #TumorBoardTuesday 7/9
NRG1 fusions are potentially targetable by drugs blocking HER:
➡️ Afatinib (pan-HER TKI)
➡️ Tarloxitinib (hypoxia-released prodrug, pan-HER inhibitor)
➡️ Zenocutuzumab (docks on HER2 and blocks NRG1-fusion binding with HER3)
➡️ Seribantumab (anti-HER3 mAb)

@TumorBoardTues POMK was a novel fusion partner and this is the only known CRC patient with an NRG1 fusion - novel fusion partners would be missed without broad tissue-based NGS/WES

@TumorBoardTues @CCR_AACR @SushmaJonna @StephenVLiu #TumorBoardTuesday 8/9
Back to our case➡️ afatinib 30 mg daily
had stable disease for 4 months with initial decline in CEA, stayed on drug for 16 months and received multiple local therapies to liver, chest wall, and duodenal lymph node

theoncologist.onlinelibrary.wiley.com/doi/10.1634/th… @OncJournal

@TumorBoardTues @CCR_AACR @SushmaJonna @StephenVLiu So sorry, I misspelled tarloxotinib!!

@TumorBoardTues @CCR_AACR @SushmaJonna @StephenVLiu @OncJournal #TumorBoardTuesday 9/9
Conclusions
➡️ Profiling can reveal rare targetable genetic alterations even in patients with known driver mutations
➡️ NRG1 fusions are seen at low frequencies across tumor types, enriched in RAS-WT panc ca
➡️ Drugs 🏹HER may have act against NRG1+ tumors

@TumorBoardTues @CCR_AACR @SushmaJonna @StephenVLiu @OncJournal