TMB-L

Great work by the team around @FilippoPietran4, @ChiaraCrem1 and @sara_lonardi1 investigating ICI in dMMR #colorectalcancer 👉TMBhigh: excellent response 👉TMBlow: poor response 👉more biomarkers needed for TMB intermediate 🧐 @OncoAlert 🚨 https://t.co/lBveXH6apZ (@heinrich_kat)

Great talk by @EricLanderMD. But sad to see that for the vast majority of early onset #colorectalcancer which is MSS TMB low, there are really not much differences in the genomic changes between early onset & average age onset #CRC #ASCO23 @OncoAlert (@manjuggm)

Great talk by Dr. Loibl on ICI in early stg TNBC 📌 low TMB tumors had greater benefit w Durvalumab compared to high TMB 📌 do we need anthracylc in TNBC in the era of IO TX ➡️ geparBOOG study ongoing 📌 ?role of adjuvant ICI s/p neoadj ICI. ➡️GeparDouze #ESMOBreast23 @OncoAlert (@MridulaGeorgeMD)

Very true Jaume! Renal cell carcinoma is a good example: lots of indels, low TMB, mostly responsive to ICPi (@RachelRiechelm2)

Showed lack of TP53 and low TMB in non smokers with SCLC. More granular data needs to be evaluated in this setting. (@thenasheffect)

It is somehow contra-intuitive to have multiple gene rearrangements and low TMB... Is the patient living in a "nuclear risk" area ? RB1 orients toward NET. Not SCLC as p53 WT. Kind of LCNEC. Regardless of pathology will treat with CT-IO and try to introduce PARP inh... (@JulienMazieres)

I definitely was concerned about SCLC when I saw the RB1 with high TF. But in a never smoker, no TP53 Mut, low TMB - not really what SCLC should look like! (@geoff_oxnard)

🔥Tumor mutational burden as a biomarker in patients with MSI #colorectalcancer treated with immune checkpoint inhibitors @OncologyAdvance https://t.co/YWWhyJ7ExW 🔎🇮🇹RWD 110 pts 👉low TMB -> cold tumors -> poor outcome 👉high TMB -> max benefit with anti-PD-1/CTLA-4 @myESMO… https://t.co/GPuu1CFTem (@ArndtVogel)

2-TP53's impact is often overlooked. But in this case, there is no TP53 loss. And I strongly recommend reading this article published in Nature this week, which reports that prognosis may be better in a group of pancreatic cancers they describe as <1mut/Mb Ultra low TMB (@UmutDisel)

But in this case, there is no TP53 loss. And I strongly recommend reading this article published in Nature this week, which reports that prognosis may be better in a group of pancreatic cancers they describe as <1mut/Mb Ultra low TMB (@UmutDisel)

RET-MAP study @JTOonline characterizes 218 pts with #RET fusion-positive NSCLC. 56% female, 93% adeno, 41% smokers, 72% with KIF5B. mTMB low (2.5 mt/Mb) and mPDL1 10%. CNS metastases in 21% at baseline, 31% overall. RR to chemo was 55% with mPFS 8.7m. https://t.co/IXBEW2NLY1 (@StephenVLiu)

Ph II TELMA trial: 1L Atezo+Bev in TMB-high NonSq NSCLC: - 307pts screened, 38 treated (149 TMB-low) - 51.3%; 72% 12m PFS & OS rates - ORR 42.1%, mDOR 11.7m - g3+ AEs 13.2% from atezo; 15.8% from bev ⁦@JAMAOnc⁩ ⁦@MARIANOPROVENCI⁩ #LCSM https://t.co/n0keHpz4t4 (@DrJNaidoo)

Once in a while we get it right. Terminal fibrolamellar cancer Rx with nivolumab/ipilimumab based on genomic/transcriptomics Non intuitive Disease failed antiPDL1, low TMB, PDL1neg 2+ yrs ongoing CR Prof Ranaan Berger credit Warms my heart See our report JITC 12/2022 (@Dr_R_Kurzrock)

@Aiims1742 what is your opinion on the chances of success of moderna mRNA personalized vaccinations against neoantigens in pancreatic cancers? they have some early success with melanoma (adding vax to immune checkpoint inhibs). will it work for adenocarcinomas with low TMB? (@P_J_Buckhaults)

Really interesting study! Heaps to unpack there. Perhaps explains why high-grade serous ovarian responds poorly - low TMB, out of control aneuploidy. Any impact of whole-genome doubling? Or protein markers in the microenvironment (PDL1 etc)? (@kylie_gorringe)

Invited abstract 635 @DrRoyHerbstYale @YaleMed reviews updates on KEYNOTE-495 randomized phase 2 in #NSCLC with pembro+lenvatinib or quavonlimab or favezelimab. Median PFS and OS were longer in T cell inf GEP nonlow TMB high subgroup @sitcancer #SITC22 (@CapitiniMD)

Happy to share our retrospective study of anti-PD1 in fibrolamellar HCC using the #Fibrolamellar Registry @SanfordMSimon https://t.co/hAWxzhaoOG ➡️ Low TMB (median 1.85 mut/MB) ➡️ Low PDL1 expression ➡️ Low but non-zero response rate to anti-PD1 (13.3% who received ICIs alone) (@MarkYarchoan)

Might be the case, however as opp to melanoma (UV damage/homogeneous high TMB)- B-Raf V600E and METex14+ NSCLC covers a more bimodal spectrum from non-smokers/low TMB to more typ IO-responsive NSCLC so considering not only mutation but underlying mol complexity might be important (@DrSteveMartin)

Indeed! METex14 (similar to B-Raf) occurs in a wider spectrum of NSCLCs from a genomic complexity standpoint (eg freq in highly IO responsive and TMB-H pulm sarc carcinoma) as compared to the homogeneously TMB-L EGFR/ALK/ROS cluster- so needs a more “holistic” view w/r tx choices (@DrSteveMartin)

🧵7 We define a cohort of TP53/RB1 wild-type SCLC tumors ➡️~5% of all SCLC ➡️TP53/RB1 WT tumors have a low TMB ➡️More frequently found in African American patients #LCSM small cell #lungcancer (@christine_lovly)

Well done study from @DrMarkAwad et al with novel findings. 1) Very high TMB (90th percentile) associated with ICI benefit, even within PDL1 0% and 1-49% subgroups. 2) Lowest TMB seen with ALK and RET. 3) KRAS with STK11/KEAP1 seen in low TMB subtypes. #LCSM (@TejasPatilMD)

Dear @pashtoonkasi @IbrahimSahinMD1 @VivekSubbiah do you think homologous recombination deficiency (POLE & POLD1 LOH) in TMB-L MSS RAS/BRAF WT mCRC could be targeted? I understand it's rare and it hasn't been studied. Any data/experience would be very appreciated. TY in any case! (@cancertrapped)

This is a Hail Mary precision oncology pass Young, non-smoker w low tmb (3), kras t50i mutated lung adenoca Very sparse info on this mutation- anyone w knowledge/experience? Eligible for any new gen Ras targeting studies? #lcsm (@DrSteveMartin)

Probably the single most important #gupath paper on MIT translocation RCCs: - low TMB, 9p21.3 alterations - worse outcome than ccrcc - ICI may be >> VEGF inh - and more @Williamson_SR @MichelleDunno17 @DrChoueiri https://t.co/m3suhjcpnB (@AkgulMd)

What is your first line treatment option for metastatic fibrolamellar HCC? Child-Pugh A5. Molecular profiling showed MSS, negative PD-L1 and low TMB at 2. No NTRK fusion. DNAJB1 pathogenic fusion and TERT promoter pathogenic variant @GABOUALFA @GIcancerDoc @pashtoonkasi (@m_khushman)

With brain Mets, young patient, ipi/Nivo vs pembro for I/O. Low TMB. Thoughts ? (@dr_ajgill)

Young, ECOG0, nonsmoker, poorly diff adeno NSCLC, multiple symp brain mets, limited lung disease, no other site of cancer, no actionable mut. PD-L1 60% low TMB. S/P WBRT What wld u do? Could u pls share ur thoughts? @JackWestMD @StephenVLiu @CharuAggarwalMD @PatelOncology #LCSM (@OncBrothers)

You can have high TMB and a shared super-antigen. You can have high TMB but no such super-antigen, aka @CharlesSwanton's branches. You can have low TMB and a shared super-antigen, aka B-cell lymphomas. TMB isn't a 'one thing' (@BettinaRyll)

Given the very low tumor mutation burdens that have repeatedly been reported in mesothelioma, we hope that greater attention is given to chromosomal rearrangements in this cancer (and in other tumors too). (@AMansfieldMD)

Exploratory trial of MSS #crc and #PancreaticCancer tmb low and use of #radiation with pd1/ctla4 to illicit out of field responses in heavily pretreated patients (@aparna1024)

to add #uvealmelanoma with very low mutational burden and very low response to #immunecheckpoint blockers (@Uli_Pfeffer)

In depth genomic and immunologic analyses were by co-first author Dr. @ValsamoA (see her excellent tweetorial!) and provide potentially groundbreaking insights into genomic drivers of response to chemo-IO in low TMB tumors like #mesothelioma 4/ (@FordePatrick)

@AMansfieldMD @MayoClinic discussing the Genomics and Epigenetics of #mesothelioma Looking past histology at genetics of mesothelioma -low TMB, Histomolecular gradients, germline BAP1 @GlopesMd @NVillamizarMD #mesothelioma #lcsm @SylvesterCancer #MIMS21 (@Latinamd)

Innovative therapy for #penilecancer-challenging rare tumor with molecular heterogeneity (HER, PI3K, Notch, DNA-repair, cell-cycle alterations), generally low TMB-VEGF+PD1i promising-HPV targeting T-cells being evaluated @JadChahoud @MoffittNews @GTumors https://t.co/IDMrUmIK0R (@sonpavde)

Tumors from patients with MSS colorectal cancer express clonal predicted neoantigens despite low TMB. However low neoantigen expression & poor T-cell priming underlie early immune escape in CRC #immunotherapy https://t.co/twsHyYYUrG (@jsoriamd)

Notably, NRG1 fusions, which are often PD-L1–low or –negative and have low TMB, are modestly responsive to a variety of cytotoxic, immune-based, and targeted therapeutic approaches. @alexdrilon @sloan_kettering #lcsm https://t.co/8K3TSJE5s7 (@OncLive)

NRG1 Fusions Confer Low PD-L1, Low TMB, and Limited Immunotherapy Responses in Lung Cancer @alexdrilon @sloan_kettering #lcsm https://t.co/yqLOtoPlmv (@OncLive)

1) With MSI-H CRC, what is the lowest TMB that you have seen where IO has worked well? 2) In MSI-H CRC, does TMB status correlate with IO response? (low TMB, IO not as efficacious?) TY @Dr_R_Kurzrock @pashtoonkasi #CRCSM (@manjuggm)

Great paper: Chuck Drake & team. Clear cell renal ca has high immune infiltrate but low TMB. The quality of the infiltrate in TME is crucial. In Cell they show subpopulatuon of macrophages are relevant in relapse. We can targeted TAMs CSF1R/CD40, but is it specific enough? (@tompowles1)

10% of patients in the study were #colorectal cancer patients "TMB in binned analyses defined low TMB as ≤5, intermediate TMB >5 and <20, high TMB as ≥20 and <50, and very high TMB as ≥50" (@fireflyann)

intrahepatic cholangio bone liver peritoneum progressed on first line chemo after 6 months, FGFR-TACC1 fusion,BAP 1,MSS,TMB low, started pemigatanib PD after 3 months. any role of alternative FGFR inhibitor? @GIcancerDoc @rachnatshroff #hpbcsm (@antonyruggeri)

Nice work from @KoheiShitara and team. Consistent with observations in @CD_AACR (https://t.co/2BgSrhKI80) @AnMinae Low TMB and PTEN mutations are predictors of a negative response to PD-1 blockade in MSI-H GI Cancers https://t.co/uf0wyERrA1 (@KlempnerSam)