Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Defects in MMR Genes as a Seminal Example of Personalized Medicine: From Diagnosis to Therapy

Microsatellite instability (MSI) is the landmark feature of DNA mismatch repair deficiency, which can be found in 15–20% of all colorectal cancers (CRC). This specific set of tumors has been initially perceived as a niche for geneticists or gastroenterologists focused on inherited predispositions. However, over the years, MSI has established itself as a key biomarker for the diagnosis, then extending to forecasting the disease behavior and prognostication, including the prediction of responsiveness to immunotherapy and eventually to kinase inhibitors, and possibly even to specific biological drugs. Thanks to the contribution of the characterization of MSI tumors, researchers have first acknowledged that a strong lymphocytic reaction is associated with a good prognosis. This understanding supported the prognostic implications in terms of the low metastatic potential of MSI-CRC and has led to modifications in the indications for adjuvant treatment. Furthermore, with the emergence of immunotherapy, this strong biomarker of responsiveness has exemplified the capability of re-activating an effective immune control by removing the brakes of immune evasion. Lately, a subset of MSI-CRC emerged as the ideal target for kinase inhibitors. This therapeutic scenario implies a paradox in which appropriate treatments for advanced disease are effective in a set of tumors that seldom evolve towards metastases.

Unexpected Favorable Outcome To Sintinib Monotherapy in A Relapse PDAC Patient With High TMB

Background Immune checkpoint inhibitors have not been widely used for pancreatic cancer treatment probably because of low immunogenic or stromal fibrotic tumor, among which only pembrolizumab was recommended for DNA mismatch repair deficiency (dMMR) by NCCN. Case presentation Here we report a 56-year-old man suffered from pancreatic ductal cancer (PDAC) with liver metastasis after radical surgery. NGS revealed remarkably high burden of TMB (49.92Muts/Mb) and microsatellite stability (MSS). Sintilimab monotherapy was continuously administrated after failure of combined chemotherapy, leading to stable disease within 22 months and few immunotherapy related AEs happened. Conclusions To our best knowledge, this is the first to report a good outcome achieving 22 months progression-free survival after PDAC metastasis with monotherapy of an immune checkpoint inhibitor. TMB may serve as a potential immunotherapy-related predictor in PDAC patients and help physicians make optimum clinical strategy.

Computed Tomography Features of Gastric Cancer Patients With DNA Mismatch Repair Deficiency

ObjectiveTo explore the computed tomography (CT) features of gastric cancer (GC) patients with DNA mismatch repair deficiency (dMMR).Materials and MethodsThis study reviewed the clinical and CT features of GC patients with dMMR, confirmed by the postoperative results, between September 2017 and December 2019. The expression pattern of MMR major proteins (MLH1, MSH2, MSH6, and PMS2) in immunohistochemistry was used to confirm the MMR status in GC tissues. The correlation between pre-treatment CT features and MMR status was statistically analyzed.ResultsA total of 28 patients with GC were diagnosed as dMMR in our study, and 49 patients were MMR-proficient (pMMR). The tumor locations were significantly different between the dMMR and pMMR groups (p = 0.006). The CT tumor thickness, CT long and short diameters of the largest lymph node, and the number of lymph nodes on CT of the dMMR group were significantly different from the pMMR group.ConclusionThe dMMR GC exhibited a lower stomach location, smaller tumor thickness and lymph node diameter, and fewer lymph nodes on CT imaging.