Rona Yaeger and Leonard Saltz
Agata A. Bielska, Walid K. Chatila, Henry Walch, Nikolaus Schultz, Zsofia K. Stadler, Jinru Shia, Diane Reidy-Lagunes, and Rona Yaeger
Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.
Anya Litvak, Andrea Cercek, Neil Segal, Diane Reidy-Lagunes, Zsofia K. Stadler, Rona D. Yaeger, Nancy E. Kemeny, Martin R. Weiser, Melissa S. Pessin, and Leonard Saltz
Routine monitoring of carcinoembryonic antigen (CEA) levels is standard in patients with resected colorectal cancer (CRC). The incidence of false-positives and the upper limits of false-positive elevations have not been previously well characterized. A search of medical records at Memorial Sloan-Kettering Cancer Center identified 728 patients who underwent an R0 resection of locoregional CRC between January 2003 and December 2012 and who had an increase in CEA level above the normal range after a normal perioperative CEA level. Of these, 358 had a false-positive elevation of CEA level, 335 had a true-positive elevation indicative of recurrent CRC, and 35 had a true-positive elevation indicative of the development of a new, non-CRC malignancy. Of those with false elevations, 111 had a single isolated CEA level elevation (median highest CEA level of 5.5 ng/mL) with no further abnormal measurements, whereas 247 had elevations on 2 or more readings, with a median highest level of 6.7 ng/mL. Of these 247 patients with confirmed false-positive CEA level elevations, only 5 (2%) had measurements greater than 15 ng/mL, and no confirmed elevation greater than 35 ng/mL was a false-positive. False-positive CEA test results in the range of 5 to 15 ng/mL are common. Confirmation of CEA elevation in this range before initiating imaging studies may be appropriate. False-positive results greater than 15 ng/mL are rare, and all confirmed CEA levels greater than 35 ng/mL were associated with cancer recurrence.