Abstract PS16-31: SKT11 loss drives rapid cancer progression and fatal pulmonary tumor thrombotic microangiopathy (PTTM) in a breast cancer patient: A case report
Authors: Fujisawa Fumie , Kunimasa Kei , Kano Rieko , Kusama Hiroki , Nishio Minako , Matsui Saki , Yoshinami Tetsuhiro , Kittaka Nobuyoshi , Nagata Shigenori , Yagi Toshinari , Nakayama Takahiro , Tamaki Yasuhiro , Imamura Fumio 
Published: February 2021

Abstract
Introduction: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cancer-associated respiratory complication characterized by widespread tumor cell emboli in small arteries and arterioles of the lung. Breast cancer is the second most common cancer causing PTTM. The pathogenesis and molecular background of PTTM have not been clarified. Here we present a case of breast cancer that experienced early onset of liver metastasis after surgical resection of the primary tumor and rapid progression leading to death due to severe respiratory distress. Autopsy was performed and it revealed that the main cause of her death was PTTM. Comprehensive next generation sequencing (NGS) analysis of the tissue obtained serially during the clinical course was performed. Case Presentation: A 48-year-old woman was diagnosed with invasive ductal carcinoma of the left breast, which was ER positive, PgR negative, and HER2 negative. FEC followed by docetaxel was administered as preoperative chemotherapy. Her tumor dramatically shrunk with chemotherapy and left partial mastectomy with left axillary lymph node dissection was performed. Histopathological analysis of the resected breast tissue revealed that there were a lot of residual cancer cells, which were ER negative, PgR negative, HER2 negative, and the result indicated that response to preoperative chemotherapy was insufficient. Additional two courses of FEC therapy were performed. Postoperative radiation therapy including the left supraclavicular lymph node area was given and adjuvant endocrine therapy with anastrozole started at the same time. At 3 months of anastrozole administration, she presented hepatic dysfunction and abnormal CT findings in the liver. Liver biopsy revealed multiple liver metastasis of breast cancer. Unresponsive to weekly paclitaxel and bevacizumab, she developed rapid respiratory failure leading to her death in two weeks. Postmortem microscopic analysis revealed an intimal fibrocellular proliferation in the pulmonary arterioles regardless of microscopic tumor emboli and extensive sinusoidal metastasis of the whole liver. NGS Analysis: We analyzed four specimens, breast cancer biopsy specimen at diagnosis, surgical resection specimen, liver needle biopsy specimen, and liver specimen obtained at autopsy, with the Ion AmpliSeq Comprehensive Cancer Panel (Thermo Fisher). The results were compared with NGS analysis of her normal lung tissue to exclude single nucleotide polymorphisms. Deep sequencing revealed that only TP53 R213* was detected as an oncogenic mutation in all four specimens. There were no mutations associated with the development of liver metastasis and her death. Comparison of the samples obtained between before and after liver metastasis revealed that STK11 loss and IKBKE amplification were harbored only in the specimens after liver metastasis. RNA sequencing analysis with the samples of initial biopsy and liver biopsy showed that the RNA expression associated with apoptosis and adhesion molecules was strongly suppressed in the liver sample. Conclusion: STK11 encodes a serine/threonine kinase, which organizes cell polarity and inhibits tumor growth. In the present patient, STK11 loss had occurred during the treatment and could induce rapid progression of her disease and PTTM.
Citation Format: Fumie Fujisawa, Kei Kunimasa, Rieko Kano, Hiroki Kusama, Minako Nishio, Saki Matsui, Tetsuhiro Yoshinami, Nobuyoshi Kittaka, Shigenori Nagata, Toshinari Yagi, Takahiro Nakayama, Yasuhiro Tamaki, Fumio Imamura. SKT11 loss drives rapid cancer progression and fatal pulmonary tumor thrombotic microangiopathy (PTTM) in a breast cancer patient: A case report [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-31.