High homogeneity of mismatch repair deficiency in advanced prostate cancer

TY - JOUR

T1 - High homogeneity of mismatch repair deficiency in advanced prostate cancer

AU - Fraune, Christoph

AU - Simon, Ronald

AU - Höflmayer, Doris

AU - Möller, Katharina

AU - Dum, David

AU - Büscheck, Franziska

AU - Hube-Magg, Claudia

AU - Makrypidi-Fraune, Georgia

AU - Kluth, Martina

AU - Hinsch, Andrea

AU - Burandt, Eike

AU - Clauditz, Till Sebastian

AU - Wilczak, Waldemar

AU - Sauter, Guido

AU - Steurer, Stefan

PY - 2020/5

Y1 - 2020/5

N2 - BACKGROUND: Recent reports have described favorable response rates for immune checkpoint inhibitors in prostate cancers with microsatellite instability (MSI). However, it is unclear whether MSI affects the entire tumor mass or is distributed heterogeneously, the latter potentially impairing treatment efficiency.METHODS: To identify prostate cancers with MSI, 316 advanced prostate cancers were analyzed by immunohistochemistry (IHC) for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6 on a TMA format.RESULTS: Out of 200 interpretable cancers, IHC findings were consistent with MSI in 10 tumors. In 9 of these 10 cancers, tissue blocks were available for subsequent large section IHC, confirming MSI in 6 cases, each with combined protein loss of MSH2 and MSH6. One additional tumor with unequivocal loss of MLH1 and PMS2 on the TMA, for which further analyses could not be carried out due to lack of tissue, was also considered to exhibit MSI. In total, 7 of 200 interpretable advanced prostate cancers were found to exhibit MMR deficiency/MSI (3.5%). Subsequent analysis of all available cancer-containing archived tissue blocks (n=114) revealed consistent and homogeneous MMR protein loss in each case. Polymerase chain reaction (PCR)-based analysis using the "Bethesda panel" could be executed in 6 MMR deficient tumors of which 4 were MSI-high and 2 were MSI-low.CONCLUSIONS: The absence of intratumoral heterogeneity for the MMR status suggests that MSI occurs early in prostate cancer. It is concluded that MMR analysis on limited biopsy material by IHC is sufficient to estimate the MMR status of the entire cancer mass.

AB - BACKGROUND: Recent reports have described favorable response rates for immune checkpoint inhibitors in prostate cancers with microsatellite instability (MSI). However, it is unclear whether MSI affects the entire tumor mass or is distributed heterogeneously, the latter potentially impairing treatment efficiency.METHODS: To identify prostate cancers with MSI, 316 advanced prostate cancers were analyzed by immunohistochemistry (IHC) for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6 on a TMA format.RESULTS: Out of 200 interpretable cancers, IHC findings were consistent with MSI in 10 tumors. In 9 of these 10 cancers, tissue blocks were available for subsequent large section IHC, confirming MSI in 6 cases, each with combined protein loss of MSH2 and MSH6. One additional tumor with unequivocal loss of MLH1 and PMS2 on the TMA, for which further analyses could not be carried out due to lack of tissue, was also considered to exhibit MSI. In total, 7 of 200 interpretable advanced prostate cancers were found to exhibit MMR deficiency/MSI (3.5%). Subsequent analysis of all available cancer-containing archived tissue blocks (n=114) revealed consistent and homogeneous MMR protein loss in each case. Polymerase chain reaction (PCR)-based analysis using the "Bethesda panel" could be executed in 6 MMR deficient tumors of which 4 were MSI-high and 2 were MSI-low.CONCLUSIONS: The absence of intratumoral heterogeneity for the MMR status suggests that MSI occurs early in prostate cancer. It is concluded that MMR analysis on limited biopsy material by IHC is sufficient to estimate the MMR status of the entire cancer mass.

U2 - 10.1007/s00428-019-02701-x

DO - 10.1007/s00428-019-02701-x

M3 - SCORING: Journal article

C2 - 31811435

VL - 476

SP - 745

EP - 752

JO - VIRCHOWS ARCH

JF - VIRCHOWS ARCH

SN - 0945-6317

IS - 5

ER -