Immune Checkpoint Inhibition as Primary Adjuvant Therapy for an IDH1-Mutant Anaplastic Astrocytoma in a Patient with CMMRD: A Case Report-Usage of Immune Checkpoint Inhibition in CMMRD

Rebekah Rittberg, Craig Harlos, Heidi Rothenmund, Anirban Das, Uri Tabori, Namita Sinha, Harminder Singh, Bernie Chodirker, Christina A Kim, Rebekah Rittberg, Craig Harlos, Heidi Rothenmund, Anirban Das, Uri Tabori, Namita Sinha, Harminder Singh, Bernie Chodirker, Christina A Kim

Abstract

Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive hereditary cancer syndrome due to biallelic germline mutation involving one of the four DNA mismatch repair genes. Here we present a case of a young female with CMMRD, homozygous for the c.2002A>G mutation in the PMS2 gene. She developed an early stage adenocarcinoma of the colon at the age of 14. Surveillance MRI of the brain at age 18 resulted in the detection of an asymptomatic brain cancer. On resection, this was diagnosed as an anaplastic astrocytoma. Due to emerging literature suggesting benefit of immunotherapy in this patient population, she was treated with adjuvant dual immune checkpoint inhibition, avoiding radiation. The patient remains stable with no evidence of progression 20 months after resection. The patient's clinical course, as well as the rational for considering adjuvant immunotherapy in patients with CMMRD are discussed in this report.

Trial registration: ClinicalTrials.gov NCT02992964.

Keywords: CMMRD; adjuvant therapy; checkpoint inhibitors; constitutional mismatch repair deficiency; immunotherapy; screening; surveillance; tumor mutational burden.

Conflict of interest statement

Authors have no relevant conflict of interest. This original research has not been presented or published previously.

Figures

Figure 1
Figure 1
FLAIR sequence axial MRI brain images. (A) 2.6 × 2.0 cm lesion in right frontal lobe (pre-operative). (B) T1 post contrast pre-operative image of right frontal lobe lesion (pre-operative) (C) Hyperintense blood products in resection bed (post-operative day 1), (D) Focal area of increased T2/FLAIR signal deep to resection cavity (prior to starting ICI, 9 months after resection). (E) T2/FLAIR hyperintense tissue changes in right frontal lobe appear stable (18 months post resection).
Figure 1
Figure 1
FLAIR sequence axial MRI brain images. (A) 2.6 × 2.0 cm lesion in right frontal lobe (pre-operative). (B) T1 post contrast pre-operative image of right frontal lobe lesion (pre-operative) (C) Hyperintense blood products in resection bed (post-operative day 1), (D) Focal area of increased T2/FLAIR signal deep to resection cavity (prior to starting ICI, 9 months after resection). (E) T2/FLAIR hyperintense tissue changes in right frontal lobe appear stable (18 months post resection).
Figure 2
Figure 2
(A) Hematoxylin and eosin stain stained section showing an infiltrating anaplastic astrocytoma, composed of mitotically active astroglial cells with enlarged, hyperchromatic, irregular nuclei (×400 magnification). On immunohistochemistry, the tumor cells are positive for mutant IDH1 R132H (B); show loss of ATRX expression in tumor nuclei (C); a small subset of tumor nuclei expressing p53 (D); complete loss of PMS2 in both normal brain tissue and neoplastic astroglial cells (E); and absence of PDL1 expression (F) (all images at ×200 magnification).

References

    1. Wang Q., Lasset C., Desseigne F., Frappaz D., Bergeron C., Navarro C., Ruano E., Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999;59:294–297.
    1. Wimmer K., Rosenbaum T., Messiaen L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin. Genet. 2017;91:507–519. doi: 10.1111/cge.12904.
    1. Bakry D., Aronson M., Durno C., Rimawi H., Farah R., Alharbi Q.K., Alharbi M., Shamvil A., Ben-Shachar S., Mistry M., et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium. Eur. J. Cancer. 2014;50:987–996. doi: 10.1016/j.ejca.2013.12.005.
    1. Liu D., Keijzers G., Rasmussen L.J. DNA mismatch repair and its many roles in eukaryotic cells. Mutat. Res. Mutat. Res. 2017;773:174–187. doi: 10.1016/j.mrrev.2017.07.001.
    1. Shiovitz S., Pritchard C.C., Jarvik G.P. Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology. Annu. Rev. Genom. Hum. Genet. 2019;20:293–307. doi: 10.1146/annurev-genom-083118-015406.
    1. Tabori U., Hansford J.R., Achatz M.I., Kratz C.P., Plon S.E., Frebourg T., Brugières L. Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood. Clin. Cancer Res. 2017;23:e32–e37. doi: 10.1158/1078-0432.CCR-17-0574.
    1. Lavoine N., Colas C., Muleris M., Bodo S., Duval A., Entz-Werle N., Coulet F., Cabaret O., Andreiuolo F., Charpy C., et al. Constitutional mismatch repair deficiency syndrome: Clinical description in a French cohort. J. Med. Genet. 2015;52:770–778. doi: 10.1136/jmedgenet-2015-103299.
    1. Kratz C.P., Holter S., Etzler J., Lauten M., Pollett A., Niemeyer C.M., Gallinger S., Wimmer K. Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome. J. Med. Genet. 2009;46:418–420. doi: 10.1136/jmg.2008.064212.
    1. Wimmer K., Kratz C.P., Vasen H.F., Caron O., Colas C., Entz-Werle N., Gerdes A.-M., Goldberg Y., Ilencikova D., Muleris M., et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: Suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD) J. Med. Genet. 2014;51:355–365. doi: 10.1136/jmedgenet-2014-102284.
    1. Suerink M., Potjer T., Versluijs A., Broeke S.W.T., Tops C., Wimmer K., Nielsen M. Constitutional mismatch repair deficiency in a healthy child: On the spot diagnosis? Clin. Genet. 2017;93:134–137. doi: 10.1111/cge.13053.
    1. Vasen H.F., Ghorbanoghli Z., Bourdeaut F., Cabaret O., Caron O., Duval A., Entz-Werle N., Goldberg Y., Ilencikova D., Kratz C.P., et al. Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D) J. Med. Genet. 2014;51:283–293. doi: 10.1136/jmedgenet-2013-102238.
    1. Durno C., Aronson M., Tabori U., Malkin D., Gallinger S., Chan H.S.L. Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred. Pediatr. Blood Cancer. 2011;59:652–656. doi: 10.1002/pbc.24019.
    1. Durno C., Boland C.R., Cohen S., Dominitz J.A., Giardiello F.M., Johnson D.A., Kaltenbach T., Levin T.R., Lieberman D., Robertson D.J., et al. Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;152:1605–1614. doi: 10.1053/j.gastro.2017.02.011.
    1. Aronson M., Gallinger S., Cohen Z., Cohen S., Dvir R., Elhasid R., Baris H.N., Kariv R., Druker H., Chan H., et al. Gastrointestinal Findings in the Largest Series of Patients with Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium. Am. J. Gastroenterol. 2016;111:275–284. doi: 10.1038/ajg.2015.392.
    1. Ercan A., Durno C., Bianchi V., Edwards M., Aronson M., Scheers I. Survival Benefit for Individuals with Constitutional Mismatch Repair Deficiency Syndrome Who Undergo a Surveillance Protocol: A Report from the International Replication Repair Deficiency Consortium. SIOP Abstr. Pediatr. Blood Cancer. 2020;67:e28742.
    1. Amayiri N., Tabori U., Campbell B., Bakry D., Aronson M., Durno C., Rakopoulos P., Malkin D., Qaddoumi I., Musharbash A., et al. High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan. Int. J. Cancer. 2015;138:380–385. doi: 10.1002/ijc.29724.
    1. Li L., Hamel N., Baker K., McGuffin M.J., Couillard M., Gologan A., Marcus V., Chodirker B., Chudley A., Stefanovici C., et al. A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype. J. Med. Genet. 2015;52:348–352. doi: 10.1136/jmedgenet-2014-102934.
    1. Campbell B.B., Light N., Fabrizio D., Zatzman M., Fuligni F., De Borja R., Davidson S., Edwards M., Elvin J.A., Hodel K.P., et al. Comprehensive Analysis of Hypermutation in Human Cancer. Cell. 2017;171:1042–1056.e10. doi: 10.1016/j.cell.2017.09.048.
    1. Bouffet E., Larouche V., Campbell B.B., Merico D., De Borja R., Aronson M., Durno C., Krueger J., Cabric V., Ramaswamy V., et al. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting from Germline Biallelic Mismatch Repair Deficiency. J. Clin. Oncol. 2016;34:2206–2211. doi: 10.1200/JCO.2016.66.6552.
    1. Bouffet E., Sudhaman S., Chung J., Kelly J., Coblentz A., Edwards M., Lipman T., Zhang C., Ercan A.B., Sambira L., et al. IMMU-18. favorable outcome in replication repair deficient hypermutant brain tumors to immune checkpoint inhibition: An international rrd consortium registry study. Neuro Oncol. 2020;22:iii363. doi: 10.1093/neuonc/noaa222.374.
    1. Bent M.J.V.D., Baumert B., Erridge S.C., Vogelbaum M., Nowak A.K., Sanson M., Brandes A.A., Clement P.M., Baurain J.F., Mason W.P., et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: A phase 3, randomised, open-label intergroup study. Lancet. 2017;390:1645–1653. doi: 10.1016/S0140-6736(17)31442-3.
    1. Mackay A., Burford A., Carvalho D., Izquierdo E., Fazal-Salom J., Taylor K.R., Bjerke L., Clarke M., Vinci M., Nandhabalan M., et al. Integrated Molecular Meta-Analysis of 1000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell. 2017;32:520–537.e5. doi: 10.1016/j.ccell.2017.08.017.
    1. Jones C., Perryman L., Hargrave D. Paediatric and adult malignant glioma: Close relatives or distant cousins? Nat. Rev. Clin. Oncol. 2012;9:400–413. doi: 10.1038/nrclinonc.2012.87.
    1. Kline C., Felton E., Allen I., Tahir P., Mueller S. Survival outcomes of pediatric high-grade glioma: Results of a 20-year systematic review and meta-analysis. J. Neuro Oncol. 2017;137:103–110. doi: 10.1007/s11060-017-2701-8.
    1. McFaline-Figueroa J.L., Braun C.J., Stanciu M., Nagel Z.D., Mazzucato P., Sangaraju D., Cerniauskas E., Barford K., Vargas A., Chen Y., et al. Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide. Cancer Res. 2015;75:3127–3138. doi: 10.1158/0008-5472.CAN-14-3616.
    1. Suwala A.K., Stichel D., Schrimpf D., Kloor M., Wefers A.K., Reinhardt A., Maas S.L.N., Kratz C.P., Schweizer L., Hasselblatt M., et al. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis. Acta Neuropathol. 2021;141:85–100. doi: 10.1007/s00401-020-02243-6.
    1. Shlien A., Campbell B.B., De Borja R., Alexandrov L.B., Merico D., Wedge D., van Loo P., Tarpey P.S., Coupland P., Behjati S., et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat. Genet. 2015;47:257–262. doi: 10.1038/ng.3202.
    1. Gong J., Chehrazi-Raffle A., Reddi S., Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. J. Immunother. Cancer. 2018;6:8. doi: 10.1186/s40425-018-0316-z.
    1. Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., Skora A.D., Luber B.S., Azad N.S., Laheru D., et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596.
    1. Touat M., Li Y.Y., Boynton A.N., Spurr L.F., Iorgulescu J.B., Bohrson C.L., Cortes-Ciriano I., Birzu C., Geduldig J.E., Pelton K., et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nat. Cell Biol. 2020;580:517–523. doi: 10.1038/s41586-020-2209-9.
    1. Lombardi G., Idbaih A., Le Rhun E., Preusser M., Zagonel V., French P. A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma? Cancers. 2020;12:3775. doi: 10.3390/cancers12123775.
    1. Khasraw M., Reardon D.A., Weller M., Sampson J.H. PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma? Clin. Cancer Res. 2020;26:5287–5296. doi: 10.1158/1078-0432.CCR-20-1135.
    1. Alharbi M., Mobark N.A., Almubarak L., Aljelaify R., AlSaeed M., Almutairi A., Alqubaishi F., Hussain M.E., Balbaid A.A.O., Marie A.S., et al. Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency. Oncologist. 2018;23:1401–1406. doi: 10.1634/theoncologist.2018-0163.
    1. Larouche V., Atkinson J., Albrecht S., LaFramboise R., Jabado N., Tabori U., Bouffet E. Sustained complete response of recurrent glioblastoma to combined checkpoint inhibition in a young patient with constitutional mismatch repair deficiency. Pediatr. Blood Cancer. 2018;65:e27389. doi: 10.1002/pbc.27389.
    1. Chung J., Maruvka Y.E., Sudhaman S., Kelly J., Haradhvala N.J., Bianchi V., Edwards M., Forster V.J., Nunes N.M., Galati M.A., et al. DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells. Cancer Discov. 2020 doi: 10.1158/-20-0790.
    1. Marabelle A., Fakih M., Lopez J., Shah M., Shapira-Frommer R., Nakagawa K., Chung H.C., Kindler H.L., Lopez-Martin J., Miller W.H., et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21:1353–1365. doi: 10.1016/S1470-2045(20)30445-9.
    1. Samstein R.M., Lee C., Shoushtari A.N., Hellmann M.D., Shen R., Janjigian Y.Y., Barron D.A., Zehir A., Jordan E.J., Omuro A., et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 2019;51:202–206. doi: 10.1038/s41588-018-0312-8.
    1. Kamiya-Matsuoka C., Metrus N., Weathers S.-P., Ross J., Shaw K., Penas-Prado M., Loghin M., Alfaro-Munoz K., O’Brien B., Harrison R., et al. Is immuno-oncology therapy effective in hypermutator glioblastomas with somatic or germline mutations? Ann. Oncol. 2019;30:v144. doi: 10.1093/annonc/mdz243.003.
    1. Johnson A., Severson E., Gay L., Vergilio J., Elvin J., Suh J., Daniel S., Covert M., Frampton G.M., Hsu S., et al. Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures. Oncologist. 2017;22:1478–1490. doi: 10.1634/theoncologist.2017-0242.
    1. Blank C.U., Haanen J.B., Ribas A., Schumacher T.N. The “cancer immunogram”. Science. 2016;352:658–660. doi: 10.1126/science.aaf2834.
    1. Lombardi G., Barresi V., Indraccolo S., Simbolo M., Fassan M., Mandruzzato S., Simonelli M., Caccese M., Pizzi M., Fassina A., et al. Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study. Cancers. 2020;12:2283. doi: 10.3390/cancers12082283.
    1. New Agent and Innovative Therapies Program (NAIT) Newsletter Early Phase Trials at SickKids. [(accessed on 15 January 2021)];2019 Available online: .

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