Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown. OBJECTIVE: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib. DESIGN, SETTING, AND PARTICIPANTS: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib. RESULTS AND LIMITATIONS: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively). CONCLUSIONS: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance. PATIENT SUMMARY: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.

Progress of hereditary breast cancer with breast cancer susceptibility gene 1/2 mutations / 肿瘤研究与临床

Hereditary breast cancer refers to malignant tumors caused by pathogenic germline mutations of breast cancer susceptibility genes (BRCA). At present, it is believed that BRCA1/2 genes are most closely related to the development of hereditary breast cancer. Mutation will lead to loss of normal function, instability of genome, and then lead to tumorigenesis. Especially for those with germline mutations, not only the risk of breast cancer will be greatly increased, but also the probability of ovarian cancer and other cancers will be increased. With the emergence and clinical application of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, BRCA1/2 genes have been regarded as new targets for the treatment of breast cancer. This article reviews the latest research of breast cancer with BRCA1/2 gene mutations.

Progress of drug resistance mechanism of poly adenosine diphosphate ribose polymerase inhibitors and the combined medication in patients with ovarian cancer / 肿瘤研究与临床

Ovarian cancer seriously threats women's health. The emergence of poly adenosine diphosphate ribose polymerase inhibitor (PARPi) has broken the barrier for ovarian cancer treatment. PARPi has been widely used and along with it comes the problem of drug resistance. Fully understanding the drug resistance mechanism of PARPi is expected to be an important way to reverse PARPi resistance. The combination of PARPi and other drugs for ovarian cancer may expand the benefits of patients using PARPi. This article reviews the drug resistance mechanism of PARPi and combined medication.

Successful treatment of refractory lung adenocarcinoma harboring a germline BRCA2 mutation with olaparib: A case report.

BACKGROUND: In recent years, targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer (NSCLC). However, the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking. CASE SUMMARY: We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation. He received gefitinib combined with six cycles of vinorelbine, cisplatin, and recombinant human endostatin as the first-line therapy. Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy, resulting in a progression-free survival (PFS) of 14 mo. Chemoradiotherapy was added following progression (enlarged brain metastases) on maintenance treatment. Unfortunately, the brain lesions were highly refractory and progressed again after 15 mo, at which time next-generation sequencing (NGS) of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations. NGS revealed that the patient harbored a BRCA2 germline mutation, the EGFR exon 19 deletion mutation disappeared, and no additional targetable genetic variant was detected. Therefore, the patient received olaparib combined with gefitinib and recombinant human endostatin, with a rapid and long-lasting clinical response (PFS = 13.5 mo). CONCLUSION: This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment, suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.

Tumor treating fields combined with a poly (adenosine diphosphate-ribose) polymerase inhibitor during radiotherapy for rapidly progressing IDH-wildtype diffuse astrocytoma: a case report.

A 57-year-old woman was diagnosed with IDH-wildtype (IDHwt) astrocytoma (World Health Organization grade II) with the molecular characteristics of glioblastoma. She underwent concurrent radiotherapy and chemotherapy according to the Stupp protocol in combination with a multi-target antiangiogenic drug and additional intrathecal chemotherapy using methotrexate. During treatment, the patient's tumor showed rapid progression. The chemotherapy with temozolomide was stopped and replaced with radiotherapy combined with tumor treating fields (TTF), the poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib, and anlotinib. After the radiotherapy was completed, the symptoms of increased intracranial pressure and epilepsy were well controlled. Considering the patient's tolerance to the treatment, the combined therapy of TTF and anlotinib was continued, and osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor with good permeability of the blood-brain barrier, was added. The patient was regularly followed up and had no obvious adverse drug reactions. Head magnetic resonance imaging (plain scan + enhanced scan) suggested that the lesions were stable. For rapidly progressing glioblastomas or histological grade II/III IDHwt astrocytomas, the combination of TTF and a PARP inhibitor during radiotherapy may have a synergistic effect on tumor control and is well tolerated by patients.

Decision analysis for secondline maintenance treatment of platinum sensitive recurrent ovarian cancer: a review.

Most women with ovarian cancer experience disease relapse, presenting numerous treatment challenges for clinicians. Maintenance therapy in the relapsed setting aims to extend the time taken for a cancer to progress, thus delaying the need for additional treatments. Four therapies are currently approved in the USA for secondline maintenance treatment of platinum sensitive, recurrent ovarian cancer: one antivascular endothelial growth factor agent (bevacizumab) and three poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (olaparib, niraparib, and rucaparib). In addition to efficacy, maintenance therapies must have a good tolerability profile and no significant detrimental impact on quality of life, as patients who receive maintenance are generally free from cancer related symptoms. Data from key bevacizumab trials (OCEANS, NCT00434642; GOG-0213, NCT00565851; MITO16B, NCT01802749) and PARP inhibitor trials (Study 19, NCT00753545; SOLO2, NCT01874353; NOVA, NCT01847274; ARIEL3, NCT01968213) indicate that bevacizumab and the PARP inhibitors are effective in patients with platinum sensitive, recurrent ovarian cancer but differ in their tolerability profiles. In addition, the efficacy of PARP inhibitors is dependent on the presence of homologous recombination repair deficiency, with patients with the deficiency experiencing greater responses from treatment compared with those who are homologous recombination repair proficient. Allowing for caveats of cross trial comparisons, we advise that clinicians account for the following points when choosing whether and when to administer a secondline maintenance treatment for a specific patient: presence of a homologous recombination repair deficient tumor; the patient's baseline characteristics, such as platelet count and blood pressure; mode of administration of therapy; and consideration of future treatment options for thirdline and later therapy.

Durable response by olaparib for a Japanese patient with primary peritoneal cancer with multiple brain metastases: A case report.

Brain metastases (BM) from epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) are extremely rare, accounting for 1-2.5% of all cases. Although therapeutic options, such as surgery, irradiation and chemotherapy are proven to yield survival benefit, the overall prognosis of these patients remains unsatisfactory. Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, olaparib is useful for patients with recurrent EOC or PPC. However, reports suggesting the efficacy of PARP inhibitors for patients with EOC or PPC with BM are limited. We report the case of a 58-year-old Japanese woman with recurrent PPC with multiple BM. After obtaining informed consent from the patient, we performed BRCA testing that detected a deleterious BRCA 1 mutation. At that time, olaparib was not yet approved in Japan, we learned about the compassionate use program of olaparib called Managed Access Program (MAP). Of note, we have established a system to enroll patients in MAP. After olaparib treatment, the patient exhibited a considerable decrease of BMs. Eighteen months since the initiation of olaparib treatment, the patient has reported no evidence of disease progression. Olaparib maintenance treatment could be effective for Japanese patients with PPC and multiple BMs.

Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

INTRODUCTION: An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. AREAS COVERED: Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. EXPERT OPINION: Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.