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Next steps includes selection based on genomic profile and improving the regimen to increase the probability of reaching a MMRd genotype and immunosensitivity

Translational analyses suggest an association between an increase in plasma TMB and MSI scores and prolonged survival in this trial. Translational analyses identified possible mechanisms precluding the acquisition of a MMRd genotype such as MMR gene amplification.

In a pilot phase I/II study, we investigated the combination of temozolomide, cisplatin and aPD1 in patients with advanced chemorefractory MMRp CRC. While we didnt observe responses, we did observe the emergence of MMRd signatures and rapid immunoediting using serial ctDNA profiling.

This resulted in high immunogenicity in multiple preclinical models, characterized by the reprogramming of the tumor immune microenvironment toward strong adaptative immunity.

In vivo, we identified that the combination of temozolomide and cisplatin was able to induce a high TMB and microsatellite instability in MMRp cells. This MMRd genotype was acquired thanks to the epigenetic loss of Msh2.

Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer Mismatch repair deficient (MMRd) tumors harbor thousands of somatic mutations enriched for insertion–deletion (indels) conferring high sensitivity to …

MMRd cancers are sensitive to ICB. What if we were able to induce a MMRd genotype in MMRp cancer cells using tailored chemical mutagenesis?

Delighted to share our two simultaneously published articles in Cancer Cell Press exploring this fundamental question!

www.sciencedirect.com/science/arti...

Dr. Violaine Randrian, a visiting investigator at MSK, spoke about a study that evaluated gene-specific outcomes in individuals with #lynchsyndrome treated with immune checkpoint blockade for advanced #cancer at #ASCO25.

Join us today at ASCO to see the fantastic work of Dr Violaine Randrian investigating what is the impact of different germline variants on outcomes derived from immunotherapy in patients with Lynch syndrome!
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The best in #GIonc trials to look for at #ASCO25. 2⃣ plenary talks that will revolutionize #crcsm and #esocsm #stmcsm. Can't wait to take this best of science into the clinic!

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Check out our article published today in the NEJM by Cercek et al. studying 6 months of anti PD1 in MMRd early stage tumors and showing high organ preservation rate pancancer! Very low recurrences and anti PD1 didn’t compromise access to surgery if required. @mskcancercenter.bsky.social

Join MSK gastrointestinal medical oncologist Dr. Andrea Cercek for a plenary session titled “Non operative management of mismatch repair deficient tumors” TODAY at #AACR25 @theaacr.bsky.social. Learn more: bit.ly/4lUDRS6

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This multidimensional assessment will allow to individualize treatment, from skipping adjuvant therapy for very low risk patients, to modulate the duration of chemotherapy or propose adjuvant therapy intensification to improve outcomes. Patients need it urgently !

The optimal assessment is currently fragmented in silos, and I believe that we need to combine multiple parameters and methods for optimal assessment. No convinient technology allows this in a single assay so far, and it is likely the future!

We comment the recent article by Gallois et al. lnkd.in/evQHVE_F introducing the idea of multidimensional prognosis assessment integrating clinical, pathological results along with ctDNA and incorporating information about tumoral microenvironment and stromal features.

Check our editorial with Andrea Cercek in the JCO on stage III colon cancer ! #coloncancer

Entering the Era of Multidimensional Prognostication for Personalized Risk Assessment in Stage III Colon Cancer | Journal of Clinical Oncology ascopubs.org/doi/full/10....

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Thanks to my co-authors Dr James R White Andrea Cercek and Luis A Diaz Jr!

Most neoadjuvant immunotherapy studies focus on short exposure, exposure being likely too short to get the best possible outcome. These important results show that longer treatment duration improves complete response rates paving the way for more organ preservation strategies.

Today in the NEJM, we report a study investigating the association between the rate of complete responses and duration of IO in MMrd cancers. Longer duration of treatment correlates with higher complete response rate in locally advanced MMRd colorectal cancer receiving anti PD1/L1 neoadjuvant IO.

Locally advanced Mismatch repair deficient cancers display extraordinary responses to neoadjuvant immunotherapy offering the opportunity when clinical complete response is observed for organ-sparing strategy. The optimal duration of treatment to reach the complete response remains unclear.

The Duration of Immunotherapy for Mismatch Repair–Deficient Cancers | NEJM An analysis of published studies suggests that a longer duration of immune checkpoint inhibitor therapy is associated with a higher incidence of complete response among patients with mismatch ...

www.nejm.org/doi/full/10....

Rectal Cancer Disappears After Experimental Use of Immunotherapy, Now an FDA Designated Breakthrough Therapy Rectal cancer patients saw their tumors disappear in a clinical trial involving immunotherapy at Memorial Sloan Kettering Cancer Center—without surgery, radiation, or chemotherapy.

A small but heralded #clinicaltrial at @mskcancercenter.bsky.social that saw #rectalcancer disappear in 100% of people who took part has taken a step towards approval by @fda.gov

#cancerresearch #oncsky