OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME

Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.

Metachronic Breast and Cerebellar Neoplasm in a Young Patient

Several factors trigger the development of genetic mutations that are responsible for causing a neoplasm. Medulloblastoma is a malignant and invasive cerebellar neoplasm, that affects children and young adults. Mucinous carcinoma is a special type of breast cancer. Being a special atypical subtype of invasive carcinoma, it most frequently affects women of advanced age and represents 1 to 7% of all breast cancers. The reported case aims to show the rarity of the occurrence of desmoplastic medulloblastoma and mammary mucinous carcinoma in a young patient in a short period of time, in different sites, without direct anatomical attachment and without occurrence of metastasis. Initially, this patient had a desmoplastic medulloblastoma and was treated with lumpectomy and radiotherapy. After 13 months, the patient was diagnosed with a mucinous breast carcinoma, underwent mastectomy, adjuvant chemotherapy and is currently undergoing endocrinotherapy. We conclude, based on the metachronous characteristic of the neoplasia and clinical characteristics, that the patient is likely to have Li-Fraumeni syndrome, an autosomal dominant disease with mutation of the TP53 gene, which is the the main involved. Because the patient does not present all the characteristics of the phenotype of the syndrome, she can thus be classified as having Li-Fraumeni variant or Li-Fraumeni-like syndrome.

Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children’s Oncology Group (ACNS1221)

PURPOSE Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. PATIENTS AND METHODS ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. RESULTS Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse—local (n= 6), distant (n = 3), and combined (n = 3)—at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age ( P = .036) and ND histology ( P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively ( P = .099). CONCLUSION The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.

Multi-nodular Desmoplastic Medulloblastoma in a Child: A Rare Radiological Physiognomy

Introduction: Nodular desmoplastic variant of medulloblastoma although very common, can present with very challenging radiological feature that mimics others lesions in the inferior and lower vermis in children. We present a case of rare radiological appearance of desmoplastic medullobastoma. Case Presentation: A one year and nine months old male presented with unstable walking and projectile vomiting of two weeks’ duration. He was apparently walking well prior this illness. The vomiting was usually in the morning and associated with headaches. Radiological imaging revealed very unusual masses in the cerebellum vermin region with obvious bilateral ventricular enlargement as well as the third ventricle, indicating hydrocephalus. Surgery was successful carried out and microscopic as well as immunohistochemistry confirmed desmoplastic medullobastoma. Conclusion: Desmoplastic medulloblastoma although not very rare can be very problematic in terms of radiological diagnosis. We are of the option that our imaging finding will throw more light on the radiological features of this tumor.

ACNS1221: A phase II study for the treatment of non metastatic desmoplastic medulloblastoma in children less than 4 years of age—A report from the Children Oncology Group.

10505 Background: Nodular desmoplastic medulloblastoma and medulloblastoma with extensive nodularity (ND/MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. Methods: We prospectively conducted a single-arm multicenter trial of conventional chemotherapy for non-metastatic ND/MBEN, based on a modified HIT SKK2000 regimen excluding the use of intraventricular methotrexate (MTX) injection, with the aim to achieve a similar outcome with reduced treatment related neurotoxicity. The design required 37 patients and targeted a 2-year PFS of ≥ 90%. Secondary objectives included evaluation of feasibility of timely central pathology review, prospective evaluation of the cohort’s molecular profile and neurocognitive outcomes. Results: Between 12/2013 and 07/2016, 26 patients were enrolled, including 16 males and 10 females, diagnosed at a median age of 19.7 months (7.1-42.9 months). Four patients had residual disease at baseline. There were 19 ND and 7 MBEN medulloblastoma, confirmed by central pathology review. All cases were reviewed within 10 days by at least 2 of the 3 neuropathologists. The study was closed early following interim analysis due to a higher than expected relapse rate. At last follow-up, 7 patients had relapsed (3 local, 2 distant and 2 combined) at a median time of 9.7 months from diagnosis (range, 9.5-13.7 months). One patient subsequently died of disease. The current median follow-up for the 25 survivors is 1 year (range, 0.2-1.9 years) and the 1 year PFS rate is 66.2% (SE 12.2%). Based on the currently available information, older age (p = 0.07) and ND histology (p = 0.009) appear to be associated with worse PFS. To date none of the patients with MBEN histology have relapsed. Conclusions: The proposed modified regimen of chemotherapy without intraventricular MTX failed to achieve the desirable 2 y PFS of 90%, leading to premature closure of the study. Ongoing molecular characterization of the cohort may help uncover patients who may still benefit from this regimen. Clinical trial information: NCT02017964.