A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors.

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Colorectal cancer (CRC) is currently one of the most common tumor types diagnosed worldwide. In the early stages, the disease responds well to surgical and chemotherapeutic treatment, but in the later stages when therapeutic options are exhausted, comprehensive genomic profiling can guide further treatment decisions. We present the case of a 46-year-old man of Ashkenazi Jewish ancestry who was diagnosed with KRAS-mutated metastatic colorectal cancer. After surgery and progression on standard FOLFOX/FOLFIRI + bevacizumab therapy, as well as on Trifluridine/Tipiracil, comprehensive genomic profiling was performed with the hope of expanding therapeutic options. Following comprehensive tumor molecular profiling via NGS, a discussion of the case was discussed at the local molecular tumor board in order to determine further treatment strategy. An activating variant of KRAS and PIK3CA, FLT3 and SRC amplification and damaging TP53 and APC variants were discarded by MTB as potential targetable biomarkers. The BRCA2 p.S1415fs*4 founder frameshift variant was of interest and the patient was included in the clinical trial investigating the efficacy of a PARP inhibitor talazoparib. Unfortunately, the disease progression was detected within one month of talazoparib treatment and the patient died during the 8th cycle of FOLFIRI + bevacizumab therapy rechallenge.

暂无摘要。

PARP inhibitors are progressively becoming a part of our therapeutic arsenal against BRCA-defective tumors, because of their capacity to induce synthetic lethality in cells with a deficiency in the homologous recombination repair system. Olaparib and talazoparib have been approved for metastatic breast cancer in carriers of germline BRCA mutations, which are found in approximately 6% of patients with breast cancer. We report the case of a patient with metastatic breast cancer, carrier of a germline mutation in BRCA2, with a complete response to first-line treatment with talazoparib, maintained after 6 years. To the best of our knowledge, this is the longest response reported with a PARP inhibitor in a BRCA-mutated tumor. We have made a review of literature, regarding the rationale for PARP inhibitors in carriers of BRCA mutations and their clinical relevance in the management of advanced breast cancer, as well as their emerging role in early stage disease, alone and in combination with other systemic therapies.

PARP inhibitors have recently emerged as a maintenance treatment option for metastatic pancreatic cancer patients with germline BRCA mutations. However, the possibility of PARP-inhibitor use as a standalone-targeted therapy for patients with various homologous repair pathway alterations remains mostly undetermined. Here we report a clinical case of a 56-year-old woman with pancreatic ductal adenocarcinoma harboring a somatic PALB2 mutation. Following disease progression after 10 cycles of FOLFIRINOX chemotherapy and two cycles of second-line gemcitabine, she was switched to talazoparib and achieved a complete clinical response after 25 months of treatment. The patient remains alive without clinical or radiological signs of disease progression three years after the start of talazoparib with no targeted therapy-related toxicities. This case highlights the role of broad molecular profiling as a window of opportunity to achieve a durable response for selected pancreatic cancer patients while pinpointing our gaps in understanding the whole picture of management of these patients since a new puzzle element represented by PARP inhibitors was introduced to clinical practice.

UNASSIGNED: The mortality rate of ovarian cancer (OC) ranks first among female genital tract malignant tumors, which seriously threatens women\'s life and health. Because of its insidious onset and poor prognosis, it has become a thorny problem in the clinic, especially for patients with platinum-resistant recurrent ovarian cancer (PROC). In recent years, the medical treatment of OC has made gratifying results, bringing hope to the patients.
UNASSIGNED: A 54-year-old OC patient who has failed previous neoadjuvant chemotherapy, cytoreductive surgery, and postoperative chemotherapy was diagnosed with PROC. Then she received combination treatment of fuzuloparib (100mg PO BID), apatinib (250mg PO QD), and camrelizumab (200mg IV Q3W) for every 3-week cycle in a Phase II study for PROC patients. In the phase II study, her condition stabilized, responded well to treatment with a sharp decrease by 91.14% of target lesions and disappearances of non-target lesions, and continued to receive regular treatment with progression-free survival exceeding 15 months and no serious adverse events.
UNASSIGNED: The present case proves PROC patients might have a sustained response to triplet combination with camrelizumab, combined with fuzuloparib and apatinib.

PARP inhibitors, such as rucaparib, have been well characterized in metastatic castration-resistant prostate cancer (mCRPC) associated with BRCA alterations, and the clinical activity of these agents has also been evaluated in patients with mCRPC associated with alterations in other non-BRCA DNA damage repair (DDR) genes, including RAD51B. There is likely a differential sensitivity to PARP inhibition based on the specific DDR gene altered, but research in this area is limited because of the low frequency of alterations in these genes. Here, we describe a mCRPC patient with a truncating rearrangement of RAD51B who had a radiographic and PSA response when treated with the PARP inhibitor rucaparib within the TRITON2 trial. We investigated the patients\' response parameters, circulating tumor DNA (ctDNA) fraction and tumor genomics longitudinally, using next-generation sequencing (NGS) of tissue and plasma. ctDNA fraction correlates with radiographic and PSA response and is lower during times of response. NGS did not reveal any potential genomic mechanism of acquired drug resistance. This case shows evidence for rucaparib activity in a rare patient with mCRPC and a RAD51B truncation.

UNASSIGNED: Brain metastases from ovarian cancer are extremely rare and have a very poor prognosis. A multimodal approach (surgery combined with radiotherapy and chemotherapy) yields the best results in reducing neurological symptoms and prolonging survival. Unfortunately, not every patient receives a complete multimodal treatment due to their individual factors. Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as a maintenance treatment option for recurrent ovarian cancer. Using PARPi may prolong the overall survival in patients with brain metastases and recurrent ovarian cancer.
UNASSIGNED: We report a case of a female patient with advanced ovarian cancer without any germline or somatic BRCA mutation. After 21 months, after reduction surgery and adjuvant chemotherapy, she was diagnosed with brain metastasis. Due to her physical fitness and economic situation, she did not receive any radiotherapy or chemotherapy but only received surgical debulking of the brain metastasis and niraparib maintenance treatment. Up to now, she has achieved a good treatment response, and the PFS is 29 months.
UNASSIGNED: Based on the response of our patient, PARP inhibitors as a single agent can probably be considered in patients with brain metastasis from ovarian cancer without BRCA mutation who cannot tolerate radiotherapy and chemotherapy.

Background: Several poly ADP ribose polymerase inhibitors (PARPis) are currently approved for the treatment of a variety of cancers. The safety profile of PARPis has not yet been systemically analyzed in the real world. We conducted this pharmacovigilance analysis using the US FDA\'s Adverse Event Reporting System (FAERS) database to explore the difference in adverse events (AEs) among PARPis. Methods: FAERS data (December 2014 to October 2021) were searched for reports of all FDA-approved PARPis across all indications. We used the standardized MedDRA query (SMQ) generalized search AEs on the preferred term (PT) level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals by calculating reporting odds ratios (ROR). Reports were considered statistically significant if the 95% confidence interval did not contain the null value. Results: Within the standardized MedDRA queries, significant safety signals were found, including those for olaparib [blood premalignant disorders (ROR = 17.06)], rucaparib [taste and smell disorders (ROR = 9.17)], niraparib [hematopoietic throbocytopenia (ROR = 28.2)], and talazoparib [hematopoietic erythropenia (ROR = 9.38)]. For AEs on the PT level, we found several significant signals, including platelet count decreased with niraparib (ROR = 52.78); red blood cell count decreased with niraparib (ROR = 70.47) and rucaparib (ROR = 15.09); myelodysplastic syndrome with olaparib (ROR = 35.47); acute myeloid leukaemia with olaparib (ROR = 25.14); blood pressure fluctuation with niraparib (ROR = 20.54); lymphangioleiomyomatosis with niraparib (ROR = 471.20); photosensitivity reaction with niraparib (ROR = 21.77) and rucaparib (ROR = 18.92); renal impairment with rucaparib (ROR = 33.32); and interstitial lung disease with Olaparib (ROR = 11.31). All the detected safety signals were confirmed using signals of disproportionality reporting methods. Conclusion: PARPis differed in their safety profile reports. The analysis of the FAERS database revealed significant safety signals that matched previously published case reports, including serious gastrointestinal, blood and lymphatic system, cardiovascular and respiratory complications, which require individualized drug administration according to patients\' conditions.