Thread by @LaurenBzak

@TumorBoardTues @JohnEbbenMDPhD 1/14 Case Presentation

63 👱‍♂️ p/w LUE & LLE weakness. CT 🧠 w/ R frontal mass.

Craniotomy and 🔪 resection ➡️ metastatic poorly-differentiated carcinoma. CT C/A/P normal.

❓What would you do next? 🧐

@NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows 2/14 #TumorBoardTuesday #OncTwitter #CUP

This is cancer of unknown primary (CUP)! ☕️

Initial evaluation of CUP includes:
🔹 H&P
🔹 CBC, CMP 🧪
🔹 CT C/A/P 📷
🔹 IHC 🔬
🔹 Optional ➡️ tumor markers, endoscopy, mammogram, PET/CT

@SamLubner @loconte @uw_hemeoncpc @OncoAlert

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert 3/14 #TumorBoardTuesday

Other history ➡️ no other sxs, 🚬 30 pack-years, no family history of cancer

The patient’s IHC findings:
🔸 CAM5.2 ➕
🔸 CK7 ➕
🔸 CK20 ➖
🔸 All other markers ➖

❓What primary site are you most suspicious of? 🕵️

@UWiscPathology @erik_rannheim

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology 4/14 #TumorBoardTuesday

CAM5.2 = carcinoma. CK7 and CK20 can help narrow 🔎 the Ddx (see table).

This patient’s IHC 🔬 is c/w 🫁, upper GI, or pancreaticobiliary primary.

Additional workup ➡️ PET/CT, EGD, all tumor markers negative. 😩

What next⁉️

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology 5/14 #TumorBoardTuesday

Can NGS help in this situation⁉️ YES‼️

NGS 🧬 can help predict tissue of origin.
pubmed.ncbi.nlm.nih.gov/33516660/

NGS 🧬 can also guide 💊 therapy! A 🎯 alteration is found in ~85% of patients with CUP.
pubmed.ncbi.nlm.nih.gov/26182302/
pubmed.ncbi.nlm.nih.gov/32457826/

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology 6/14 #TumorBoardTuesday

🌟 Site-specific or molecularly-targeted 🎯 therapy for CUP may ⬆️ PFS and OS‼️ 🤯
pubmed.ncbi.nlm.nih.gov/23032625/
pubmed.ncbi.nlm.nih.gov/33057591/
pubmed.ncbi.nlm.nih.gov/27575023/

📣 Bottom line? Think NGS 🧬 when treating CUP.

@JCO_ASCO @JAMAOnc @TheLancetOncol

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol 7/14 #TumorBoardTuesday

Our patient’s NGS 🧬 results…
✳️ MSI stable
✳️ TMB 20 m/mB
✳️ PDGFRA amplification
✳️ TP53 c.388C>T (53%)
✳️ STK11 c.468C>A (59%)
✳️ SMARCA4 c.3554_3556delinsCAT (38%)

🔬 PD-L1 20%

What is the most likely tissue of origin?

@TheFellowOnCall

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall 8/14 #TumorBoardTuesday

GERMLINE 🧬 mutations in STK11 (aka LKB1) are found in Peutz-Jeghers syndrome (PJS).

PJS features:
🔹 GI hamartomatous polyps
🔹 Mucocutaneous pigmentation
🔹 Malignancy ➡️ CRC, breast, ovary, pancreas

Our patient’s presentation is not c/w PJS.

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall 9/14 #TumorBoardTuesday #STK11

SOMATIC 🧬 mutations in STK11 can be seen in ~25% of NSCLC. ​​🫁

Characteristics of STK11-mutant 🫁 tumors…
🔸 Smokers 🚬
🔸 Adenocarcinoma (rare in SCLC)
🔸 Less differentiated
🔸 Other mutations (TP53, KRAS, etc.)

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall 10/14 #TumorBoardTuesday

The SMARCA4 variant is also interesting. 🧐

A subset of poorly-differentiated 🫁 adenocarcinomas show SMARCA4 mutations, TP53 mutations, and high TMB due to 🚬 exposure.
pubmed.ncbi.nlm.nih.gov/28555282/
pubmed.ncbi.nlm.nih.gov/31751681/

Sound familiar⁉️

@IASLC

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall @IASLC 11/14 #TumorBoardTuesday #STK11

Our patient’s NGS 🧬 results are pretty convincing for 🫁 cancer. What does this mean in regard to prognosis? 🤷🏽‍♀️

STK11 mutations associated with…
⬇️ Response to IO
⬆️ Recurrence
⬇️ PFS and OS

Yikes! 😱

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall @IASLC 12/14 #TumorBoardTuesday #PrecisionMedicine

No 🎯 therapy for STK11 available right now, but many clinical trials 🧪 in process…🤞

Good reviews on STK11 in 🫁 cancer:
pubmed.ncbi.nlm.nih.gov/35165542/
pubmed.ncbi.nlm.nih.gov/32396674/

@CureusInc @OncJournal

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall @IASLC @CureusInc @OncJournal 13/14 #TumorBoardTuesday

Back to our patient 👱‍♂️

🔸 XRT to resection bed
🔹 Presented w/ LUE weakness 3 months later
🔸 🧠 recurrence ☹️
🔹 Re-resection 🔪 and XRT
🔸 Still no evidence of systemic disease
🔹 Soon to start IO due to ⬆️ TMB 🤞

How would you manage this patient❓

@TumorBoardTues @JohnEbbenMDPhD @NSethakorn @NarjustDumaMD @HamidEmamekhoo @KariWisinski_MD @HemOncFellows @SamLubner @loconte @uw_hemeoncpc @OncoAlert @UWiscPathology @JCO_ASCO @JAMAOnc @TheLancetOncol @TheFellowOnCall @IASLC @CureusInc @OncJournal 14/14 #TumorBoardTuesday #CUP #STK11

What did we learn❓
🚨 NGS can identify CUP tissue of origin
🚨 NGS can find druggable 💊 targets 🎯
🚨 STK11 is common in 🫁 cancer
🚨 STK11 often co-mutated w/ KRAS, TP53
🚨 STK11 a/w ⬇IO response and survival

📣 Think NGS 🧬 in CUP‼️