ANTI-PD-1 Treatment in a Family with Constitutional Mismatch Repair Deficiency Syndrome with Multiple Cancers from Turkey. Is Cancer Immunoprevention with Checkpoint Inhibitors HAS a Role in CASES with Homozygous Mutationis
Authors: Unal Emel , Ozyoruk Derya , Tacyildiz Nurdan , Pi̇narli̇ Ferda , Erdogan A , Hanalioglu S , Erdem Arzu , Beksac Meral 
Published: November 2019

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations of MMR genes and it is poorly recognised by clinicians so far. Here we present affected children of 1st degree consanguinous parents diagnosed with CMMRD syndrome due to germline bi-allelic MSH 6 mutations with multiple cancers and mimicking NF 1 in a family from Turkey
A 8-yr-old female,referred with brain tumor with follow up Neurofibromatosis 1 and Familial Mediterranean Fever. One of the female siblings had died of aggressive brain tumor at 4yrs of age, one male sibling due to medulloblastoma, followed by diagnosis of a metachronous metastatic colon adenocarcinoma at 15yrs of age. No additional cancers have been reported in the extended family, with the exception of colorectal cancer in the maternal and paternal great uncle diagnosed at age 45 years, paternal grandfather with brain tumor at 70 age of years and maternal aunt with papillary thyroid cancer at age 50 years.
Her physical examination was unremarkable other than 8 to 10 cafe-au- lait spots and hipodense macules with irregular borders on her body. Laboratory tests were normal with low IG G2 levels. Cranial MRI revealed a mass in the left cerebellar region, subcortical hyperdens lesions in fronto-parietal area. She underwent near-total resection,histopathology revealed classic desmoplastic medulloblastoma.Postoperative craniospinal MRI showed no residue or metastasis.Craniospinal RT and CT of CCNU, cisplatin,VCR were given. At initial, due to colon adenocarcinoma history in her family, the colonoscopy was performed which did not reveal any polypoid lesions. In addition, because of the family history, the genetic analysis was carried out and disclosed a novel homozygous single base insertion mutation in exon 5 of the MSH 6 gene ( c.3261dupC/ p.Phe1088Leu ).Five cycles of previously mentioned chemotherapy combination and Nivolumab, obtained by pediatric extended use, was commenced at 3 mg/kg/dose in every 2 weeks as new polyps were detected in the following colonoscopy. After 10th dose,9 polyps were removed of tubular adenoma histopathology .She is still on antiPD1 treatment (18.th dose and in remission. Last colonoscopy revealed only one polyp mm in size. The genetic test results of the family: Blood samples were obtained from parents and siblings. One of the siblings was also found to be homozygous. She is 24- months- old age and has multiple cafe-au-lait spots on her body. She is still under follow up with screening tests for development of possible neoplasms. The parents and the other two siblings ( 11 and 6 years old boys) were heterozygous for the mutation. The male sibling who died from medulloblastoma and metastatic colorectal carcinoma genetic test had revealed same homozygous mutation.
Conclusions:
As the use of immune modulation for cancer prevention rather than therapy has gained considerable attention, we wonder if 24-months-old female sibling with homozygous mutation will be a candidate for cancer immunoprevention with AntiPD1drugs. We think that an international collaboration is required to evaluate guidelines for screening and treatment of malignancies and to explore prevention strategies patients with CMMRD syndrome.

Disclosures
Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau.