@mskcancercenter.bsky.social
Swim across America

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.

@mskcancercenter.bsky.social

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.

@mskcancercenter.bsky.social
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.