After completing this course, the reader will be able to:1. Evaluate the level of evidence to inform decision making for the treatment radiation induced sarcoma of the breast.2. Explain diagnostic criteria for radiation-induced sarcoma.3. Describe the effectiveness of surgery, chemotherapy and radiation therapy for radiation induced sarcoma of the breast.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTIntroduction. Radiation-induced sarcoma (RIS) is a rare, aggressive malignancy. Breast cancer survivors treated with radiotherapy constitute a large fraction of RIS patients. To evaluate evidenced-based practices for RIS treatment, we performed a systematic review of the published English-language literature. Methods. We performed a systematic keyword search of PubMed for original research articles pertaining to RIS of the breast. We classified and evaluated the articles based on hierarchal levels of scientific evidence.Results. We identified 124 original articles available for analysis, which included 1,831 patients. No randomized controlled trials involving RIS patients were found. We

Both the regimens showed expected PFS and numerically comparable overall survival. Quality of life was similar in the two arms, and both the regimens were well tolerated.

Background Radiation-induced sarcoma (RIS) is a potential complication of cancer treatment. No widely available cell line models exist to facilitate studies of RIS. Methods We derived a spontaneously immortalized primary human cell line, UACC-SARC1, from a RIS. Results Short tandem repeat (STR) profiling of UACC-SARC1 was virtually identical to its parental tumor. Immunohistochemistry (IHC) analysis of the tumor and immunocytochemistry (ICC) analysis of UACC-SARC1 revealed shared expression of vimentin, osteonectin, CD68, Ki67 and PTEN but tumor-restricted expression of the histiocyte markers α1-antitrypsin and α1-antichymotrypsin. Karyotyping of the tumor demonstrated aneuploidy. Comparative genomic hybridization (CGH) provided direct genetic comparison between the tumor and UACC-SARC1. Sequencing of 740 mutation hotspots revealed no mutations in UACC-SARC1 nor in the tumor. NOD/SCID gamma mouse xenografts demonstrated tumor formation and metastasis. Clonogenicity assays demonstrated that 90% of single cells produced viable colonies. NOD/SCID gamma mice produced useful patient-derived xenografts for orthotopic or metastatic models. Conclusion Our novel RIS strain constitutes a useful tool for pre-clinical studies of this rare, aggressive disease. UACC-SARC1 is an aneuploid cell line with complex genomics lacking common oncogenes or tumor suppressor genes as drivers of its biology. The UACC-SARC1 cell line will enable further studies of the drivers of RIS. Synopsis We derived a spontaneously immortalized primary human cell line, UACC-SARC1, from a radiation-induced sarcoma (RIS). Our novel RIS cell line constitutes a useful tool for pre-clinical studies of this rare, aggressive disease.

196 Background: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer, accounting for 5% of breast cancers diagnosed annually in the United States. Understanding the distinct biology of IBC could help provide novel treatment targets. We sought to evaluate whether or not the IBC cell lines SUM 149 and SUM 190 demonstrated evidence of viral infection. Methods: We performed single nucleotide polymorphism (SNP) genotyping for 2 variants of the ribonuclease (RNase) L gene that have been correlated with the risk of prostate cancer due to a possible viral etiology. We also performed proliferation assays; developed dose response curves to assess the treatment effect of interferon-alpha (IFN-a); and assayed for evidence of the putative human mammary tumor virus (HMTV, which has been implicated but not definitively associated with IBC,) in the DNA and RNA of SUM 149 cells. Results: According to our allelic discrimination SNP assay, 2/2 IBC cell lines were homozygous for the 462 and 541 variants, whereas 0/10 non-IBC cell lines were homozygous positive for the 462 variant (p = 0.015) and 2/10 non-IBC cell lines contained homozygous alleles for the 541 variant (p = 0.52). We also found a dose and time-dependent decrease in the proliferation of SUM 149 IBC cells treated with IFN-a. In contrast, non-IBC cell lines did not show a dose-response decrease in cell proliferation. Our reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blot analysis for the env/LTR and late LTR sequences of the putative HMTV revealed no evidence of the putative viral genome. Conclusions: We discovered 2 SNPs, in the 462 and 541 variants of the RNase L gene, that were homozygously mutated in IBC cell lines but the 462 variant was absent in non-IBC lines. Our discovery of these mutated SNPs present in IBC cell lines suggests a possible genetic risk factor for IBC. In our study, the IBC cell line SUM 149 demonstrated a direct and specific response to treatment with IFN-a, an antiviral agent. We noted no evidence of HMTV infection in that cell line. Further studies of the prevalence and significance of the RNase L 462 and 541 variants in human IBC tissue specimens are warranted to validate our in vitro findings.

MEN1 is an autosomal dominant syndrome characterized by involvement of several endocrine and non-endocrine organs. The most common endocrine organs that are affected include pituitary, parathyroid, and/or pancreas. In 10-30% of patients, no germline mutations in the menin gene are identified, presenting a diagnostic challenge. This case raises the question of possible MEN4 syndrome, which shares a similar phenotype to MEN 1 with germline mutation in CDKN1B. Clinical case 59 y/o female with PMH HTN, obesity, hypothyroidism initially presented to our clinic in 2018 for evaluation of hypercalcemia. She prior was seen in 2005 for evaluation of prolactinoma by outside endocrinologist but was lost to follow up. Per history, she had a pituitary MRI in 1991 for work up of amenorrhea and found to have prolactinoma. She was placed on bromocriptine at that time; after repeat pituitary MRI and prolactin levels were found to be normal, bromocriptine was discontinued in 2019 but then restarted a few months later due to uptrending prolactin level. During the visit with us, work up for her hypercalcemia included calcium of 11. 0 mg/dL and PTH level of 93 pg/mL with normal albumin, vitamin D, and renal function. Patient had a negative sestamibi scan but was found to have a 10 mm×5 mm×12 mm enhancing nodule along the left thyroid gland and along left lateral margin of esophagus, suggesting parathyroid adenoma. She subsequently underwent successful left inferior parathyroidectomy in July 2019 with normalization of calcium and PTH levels. No other parathyroid was found to be enlarged. Given her pituitary and parathyroid adenoma, she was sent for genetic testing; she was evaluated for 7 gene variants and all were found negative including MEN1, CDKN1B, GNA11, AP2S1, CASR, CDC73, and RET. Of note, she has no family history of MEN1 or any endocrine tumors. However, further testing was still performed to evaluate for a pancreatic neuroendocrine tumor including CT abdomen, gastrin, C peptide, chromogranin-A, glucagon, VIP, and 5-HIAA. Her initial testing came back normal including normal CT abdomen in 2020. However, her most recently lab results in 2021 revealed an elevated gastrin level of 124 pg/mL and uptrending chromogranin A of 262 ng/mL (<=93), the diagnosis of gastrinoma was confirmed and PPIs were started. Discussion This case highlights the importance of continued surveillance in patients with multiple endocrine organ involvement or neoplasia despite negative genetic testing; it also supports the likelihood of unidentified mutations given the improbable chance this patient has 3 independent endocrine tumors. Possibilities including missed germline mutations on testing or phenocopies. This patient likely has an upstream mutation that was not identified and could represent either MEN1 vs MEN4 Presentation: No date and time listed

Background: Radiation-induced sarcoma (RIS) is a potential complication of cancer treatment. No widely available cell line models currently exist to facilitate studies of RIS. Methods: We derived a primary human cell line, UACC-SARC1, from a RIS. Short tandem repeat (STR) genotyping was used to confirm that this cell line was propagated from the tumor. Further characterization of this cell line involved comparing 24 markers using immunocytochemistry (ICC) to immunohistochemistry (IHC) of the tumor, a Matrigel invasion assay, karyotyping of the cell line, comparative genomic hybridization (CGH), DNA sequencing using the Ion AmpliSeq Cancer panel and in vivo mouse xenografts after subcutaneous injection of UACC-SARC1 in immunodeficient mice. Results: STR profiling of UACC-SARC1 was virtually identical to its parental tumor. IHC analysis of the tumor and ICC analysis of UACC-SARC1 revealed shared expression of vimentin, osteonectin, CD68, Ki67 and PTEN but tumor-restricted expression of the histiocyte markers α1-antitrypsin and α1-antichymotrypsin. Karyotyping of the tumor demonstrated aneuploidy. CGH provided direct genetic comparison between the tumor and UACC-SARC1. Sequencing of 740 mutation hotspots revealed no mutations in UACC-SARC1 nor in the tumor. SCID mice xenografts exhibited tumor formation but resulting tumors failed to metastasize. Further xenografts with NOD SCID gamma (NSG) mice are planned. The doubling time of UACC-SARC1 was 28.3 hours. Conclusion: Our novel RIS strain constitutes a useful tool for pre-clinical studies of this rare, aggressive disease. Citation Format: Julie E. Lang, Brandon Nokes, Grishma Sheth, Petr Novak, Laura Fuchs, George S. Watts, Bernard W. Futscher, Neal Mineyev, Weizhu Zhu, Lauren LeBeau, Ray Nagle, Lee Cranmer. Characterization of a novel radiation-induced sarcoma cell line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1200. doi:10.1158/1538-7445.AM2014-1200