Hanaoka Taro, Okuwaki Kosuke, Nakamura Kohei, Okada Shunji, Nishizawa Nobuyuki, Watanabe Masafumi, Iwai Tomohisa, Adachi Kai, Kumamoto Yusuke, Kusano Chika
Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa 252-0374 Japan.
Genomics Unit, Keio Cancer Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582 Japan.
Int Cancer Conf J. 2024 Aug 16;13(4):493-498. doi: 10.1007/s13691-024-00715-0. eCollection 2024 Oct.
A 54-year-old man with resectable pancreatic cancer and abnormally high levels of carbohydrate antigen 19-9 (CA19-9) underwent 6 months of platinum-based chemotherapy. This treatment substantially reduced the primary tumor size and normalized CA19-9 levels. Subsequently, radical surgery was conducted. However, eight months post-surgery, CA19-9 levels re-elevated, and lymph-node recurrence was observed. The patient underwent treatment with poly(adenosine diphosphate ribose) polymerase inhibitors (PARPi) following the detection of frameshift L1904fs5 via BRACAnalysis CDx. This mutation revealed a stop codon, leading to the inactivation of the function. Additionally, the patient tested positive for a mutation in the breast cancer susceptibility gene 2 (). Two months after starting PARPi, there was evidence of tumor shrinkage. Nevertheless, 5 months later, CA19-9 levels increased again, and new metastatic tumors in the liver were identified. Genomic profiling test (FoundationOne CDx) of surgically resected specimens revealed a pL1908fs2 mutation, indicating its location in the cis position on the same allele as the germline mutation. The pL1908fs2 deletion, alongside the original L1904fs5, resulted in three deletions, equating to one amino acid deletion. This deletion ultimately reversed the stop codon, leading to the restoration of functionality. Despite treatment with PARPi for postoperative recurrence, a sustained response was not achieved owing to reversion mutations. It is essential to acknowledge the rarity of reversion mutations, which limit the effectiveness of PARPi.
一名54岁的可切除胰腺癌男性患者，其碳水化合物抗原19-9（CA19-9）水平异常升高，接受了6个月的铂类化疗。该治疗显著缩小了原发肿瘤大小，并使CA19-9水平恢复正常。随后进行了根治性手术。然而，术后8个月，CA19-9水平再次升高，并观察到淋巴结复发。在通过BRACAnalysis CDx检测到移码L1904fs5后，该患者接受了聚（腺苷二磷酸核糖）聚合酶抑制剂（PARPi）治疗。这种突变揭示了一个终止密码子，导致功能失活。此外，该患者乳腺癌易感基因2（）的突变检测呈阳性。开始使用PARPi两个月后，有肿瘤缩小的迹象。然而，5个月后，CA19-9水平再次升高，并且在肝脏中发现了新的转移瘤。手术切除标本的基因组分析测试（FoundationOne CDx）显示存在pL1908fs2突变，表明其位于与种系突变相同等位基因的顺式位置。pL1908fs2缺失与原始的L1904fs5一起，导致三个缺失，相当于一个氨基酸缺失。这种缺失最终逆转了终止密码子，导致功能恢复。尽管使用PARPi治疗术后复发，但由于回复突变，未实现持续缓解。必须认识到回复突变的罕见性，这限制了PARPi的有效性。
