The mechanism and progress of PARP inhibitors in the treatment of advanced breast cancer / 中国肿瘤临床

Poly ADP-ribose polymerase (PARP) inhibitors can block the repair of DNA single-strand breaks, and BRCA mutation can cause the loss of repair function of DNA double-strand damage in breast cancer cells. Therefore, PARP inhibitors are used to treat BRCA-mutant breast cancer by simultaneously blocking the repair of DNA single-strand breaks and DNA double-strand damage, which leads to the failure of DNA repair, resulting in the death of cancer cells. At present, a variety of PARP inhibitors have been developed that primarily inhibit PARP1 and PARP2 subtypes with high sensitivity and specificity. This review summarizes the mechanism of PARP inhibitors in the treatment of breast cancer with BRCA mutation, and states the progress of several reported PARP inhibitors used alone or in combination with commonly used chemotherapeutic agents for the treatment of advanced breast cancer.

Checkpoint-inhibition in ovarian cancer: rising star or just a dream? / 부인종양

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.

Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management

Ovarian cancer patients with homologous recombination deficiencies exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors, have been observed. Germline mutations in the BRCA 1/2 genes are the most well-known mechanisms of homologous recombination deficiency. However, other mechanisms, such as germline and somatic mutations in other homologous recombination genes and epigenetic modifications, have also been implicated in homologous recombination deficiency. The epidemiology and implications of these other mechanisms need to be better understood to improve the treatment strategies for these patients. Furthermore, an evaluation of various diagnostic tests to investigate homologous recombination deficiency is essential. Comprehension of the role of homologous recombination deficiency in ovarian cancer also allows the development of therapeutic combinations that can improve the efficacy of treatment. In this review, we discuss the epidemiology and management of homologous recombination deficiency in ovarian cancer patients.

BRCA1-mutated ovarian cancer with skin metastasis: a case report

The major risk factor for ovarian cancer (OC) is mutation of the BRCA1 or BRCA2 DNA mismatch repair genes, which occurs in approximately 10% of OC cases. Most previous studies have demonstrated that BRCA1- and BRCA2-mutated OCs are associated with better prognosis than sporadic OCs. However, information about the patterns and clinical course of the metastatic spread of BRCA-mutated OCs is limited. Herein, we describe a case of OC with a BRCA1 mutation and skin metastases in a 49-year-old patient, which to the best of our knowledge has not been reported previously.

Regulatory mechanisms of the radiosensitive effect of PARP-1 inhibitor on breast cancer cells with BRCA mutation / 中华放射医学与防护杂志

Objective To investigate the radiosensitivity effects of poly ADP-ribose polymerase-1 (PARP-1) inhibitor 3-amion benzamide (3-AB) on the BRCA non-mutant and BRCA mutant breast cancer cells,and to explore the regulatory mechanism of PARP-1 and BRCA in radiation-induced DNA damage repair.Methods MDA-MB-436 cells and MDA-MB-231 cells were divided into four groups respectively as the control (CTRL),ionizing radiation alone (IR),3-AB alone (3-AB),and ionizing radiation combined with 3-AB(IR + 3-AB)group.γ-H2AX foci were detected by immunofluorescence assay.The radiosensitivity of breast cancer cells was evaluated by clonogenic survival assay.The percentage of apoptotic cells was assessed by flow cytometry.Results Compared with MDA-MB-231 cells,MDA-MB-436 cells had a higher radiosensitivity and produced more γ-H2AX foci(t =4.57,P ＜ 0.05),which was further increased by 3-AB.The DNA damage of MDA-MB-436 cells in the IR + 3-AB group was the most remarkable (t =3.26,P ＜ 0.05).Flow cytometry showed that the cells in the IR + 3-AB group had the highest rate of apoptosis (t=3.81,P ＜ 0.05),and the apoptosis rate of MDA-MB-436 cells was significantly higher than MDA-MB-231 cells (t =2.96,P ＜ 0.05).Conclusions The radiosensetivity of BRCA mutant cells MDA-MB-436 is significantly higher than that of non-BRCA mutant cells MDA-MB-231.Inhibition of PARP-1 can further increase the apoptosis and radiosensitivity of BRCA-mutant cells by further blocking the repair of DNA single-strand break induced by ionizing radiation.

Magnetic Resonance Imaging of Breast Cancer Patients with BRCA Mutation

PURPOSE: To evaluate the MRI findings of breast cancer with BRCA mutation. MATERIALS AND METHODS: We collected information of the breast cancer patients who underwent the test for BRCA gene mutation as well as preoperative breast MRI from January 2007 to December 2010. A total of 185 patients were enrolled; 33 of these patients had BRCA mutations and 152 patients did not. Among them, a total of 231 breast cancers were detected. Images of the 47 breast cancers with BRCA mutation and of the 184 breast cancers without mutations were evaluated to compare the morphologic and enhancement features on MRI. RESULTS: With MR imaging, there were no significant difference in morphologic characteristic between two groups. However, enhancement pattern in the group with BRCA mutation were more likely to have persistent enhancement (p < 0.233), and LN metastasis was more common in breast cancers without BRCA mutation. Breast cancers with BRCA 2 mutation tend to show more persistent enhancement pattern than BRCA 1 mutation. CONCLUSION: In breast cancer patients with BRCA mutation, MRI didn't show significant difference in morphologic characteristics, however breast cancers with BRCA gene mutation carriers tend to have benign morphologic features on MRI, such as Type 1 kinetic curve enhancement.

One Case of BRCA2 Germline Mutation Ovarian Cancer Mother and Carrier Daughter found by Genetic Counseling

Among cause of carcinogenesis, heredity is believed to take about 10 percent in ovarian cancer. BRCA1 or BRCA2 account for largest portion of Hereditary Breast and Ovary Cancer (HBOC). Frequency of BRCA1/2 germ line mutations varies according to region and ethnicity from 1.1-39.7 percent. The identification of ovarian cancers with a BRCA mutation is will be more and important due to the possibility to offer a genetic counseling and also due to potential beneficial treatment effects with a poly-ADP-ribose polymerase inhibitor in some individuals. We report the case of a 41 year old woman with a stage Ic mucinous ovarian adenocarcinoma and carrier daughter found on family genetic counseling. We indentified other family members with a history of breast cancer of 1st degree and pancreatic cancer of 2nd degree relative. After a screening with immunohistochemistry, the absence of nuclear expression for BRCA1 and BRCA2 was revealed. The gene sequencing confirmed heterozygous mutations of BRCA2 gene. The daughter of the case subject consented for a test. This test was shown the daughter is positive for BRCA2 mutation. Regular surveillance, chemoprophylaxis with oral contraceptive and prophylactic surgery after childbearing were offered to her.

Hereditary Breast Cancer in Korea

About 7% of all breast cancer (BC) cases result from a genetic predisposition, and approximately 1,000 patients develop hereditary BC (HBC) every year in Korea. BRCA1 and BRCA2 are the primary genes underlying HBC. The average cumulative risks in BRCA1 mutation carriers at 70 years of age are 65% (95% confidence interval 44-78%) for BC and 39% (18-54%) for ovarian cancer (OC). The corresponding estimates for BRCA2 are 45% (31-56%) and 11% (2.4-19%), respectively. The penetrance of BRCA mutations is not the same between patients and can depend on factors such as race and birth-cohort. The Korean Hereditary Breast Cancer (KOHBRA) study is a large prospective nationwide study that includes 39 participating centers. Between May 2007 and May 2010, the first phase of the KOHBRA study was planned and fulfilled successfully. The primary aim of phase I was to estimate the prevalence of BRCA1/2 mutations and OC among a high-risk group of patients with HBC and their families. According to data collected during phase I of the study, the prevalence and penetrance of BRCA mutations were comparable to corresponding data from Western countries. For the second phase of the KOHBRA study, we are currently investigating a Korean BRCA mutation prediction model, prognostic factors in BRCA-related BC, environmental/genetic modifiers, and implementing a genetic counseling network. The final goal of the KOHBRA study is to create clinical practice guidelines for HBC in Korea. In this article, I review the genetics of HBC, summarize the characteristics of Korean HBC, and discuss current and future HBC research in Korea.

Evaluation of Psychosocial Impact and Quality of Life in BRCA Mutation Family

PURPOSE: The aims of this study are to evaluate psychological impact and quality of life according to the cancer diagnosis and mutation status in Korean families with BRCA mutations. MATERIALS AND METHODS: Seventeen affected carriers (AC), 16 unaffected carriers (UC) and 13 healthy non carriers (NC) from 13 BRCA mutation families were included in the study. Outcomes were compared with regard to depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory, STAI), optimism (Reevaluation of the Life Orientation test, LOT-R), knowledge of hereditary ovarian cancer, and quality of life (QoL) (SF-36v2 Health Survey, physical component score [PCS], mental component score [MCS]) among three groups. RESULT: Level of depression, optimism, and PCS were similar in AC, UC, and NC. Anxiety score was elevated in all three groups. MCS was significantly low in AC than in UC and NC (P =0.009, P =0.017). Knowledge of hereditary breast and ovarian cancer was high in AC than NC (P =0.001). MCS was significantly related to whether patient was affected by cancer (P =0.043) and has occupation (P = 0.008) or not in multivariable analysis. CONCLUSION: From this cross sectional study, psychological adverse effect was not related to the carrier status of BRCA mutation. Elevated anxiety in BRCA family members was observed but, independent to affection and the type of genetic mutation. AC showed low mental QoL. Further effort to understand psychological impact and QoL of genetic testing in BRCA family members is required for follow-up in clinical aspects.

The Breast and Ovarian Cancer Risks in Korea Due to Inherited Mutations in BRCA1 and BRCA2: A Preliminary Report / 한국유방암학회지

PURPOSE: To estimate the cumulative risk till each age (penetrance) of breast and ovarian cancers among female family members with BRCA1 and BRCA2 mutation. METHODS: Among the 61 BRCA1 mutation carriers in the 42 families and 47 BRCA2 mutation carriers in 31 families identified at 5 academic breast clinics, the probands were excluded to estimate the cumulative risk till each age of breast cancer in the Korean BRCA1 and BRCA2 carriers. Using Kaplan-Meier analyses, cumulative cancer risk estimates were determined. RESULTS: By the age 70, the female breast cancer risk for the BRCA1 and BRCA2 mutation carriers was 72.1% (95% confidence interval [CI]=59.5% to 84.8%) and 66.3% (95% CI=41.2% to 91.5%), respectively, and the ovarian cancer risk was 24.6% (95% CI=0% to 50.3%) and 11.1% (95% CI=0% to 31.6%), respectively. The contralateral breast cancer risk at 5 years after primary breast cancer was estimated as 16.2% (95% CI=9.3% to 23.1%) for the 52 breast cancer patients with the BRCA1 mutation and 17.3% (95% CI=9.7% to 24.0%) for the 35 breast cancer patients with the BRCA2 mutation. CONCLUSION: The penetrance of BRCA mutations in Korea is largely consistent with the previous studies on Western populations. However, the small number of the cases, the high proportions of probands in the study subjects, the short term follow-up, and large confidence intervals are the limitations of the current study. The Korean Hereditary Breast Cancer Study (KOHBRA Study) may definitely answer this question.

Is the BRCA Germline Mutation a Prognostic Factor in Korean Patients with Early-onset Breast Carcinomas? / 대한방사선종양학회지

PURPOSE: The purpose of this study was to determine if there were prognostic differences between BRCA related and BRCA non-related Korean patients with early-onset breast carcinomas. MATERIALS AND METHODS: Sixty women who had developed breast cancers before the age of 40, and who were treated at the Soonchunhyang University Hospital, were studied independently of their family histories. The age range was 18 to 40 with a median of 34.5 years. Lymphocyte specimens from peripheral blood were studied for the heterozygous mutations of BRCA1 and BRCA2 using direct sequencing methods. Immunohistochemistry was performed on the paraffin-embedded tissue blocks that were available. RESULTS: Eleven deleterious mutations (18.3%, 6 in BRCA1 and 5 in BRCA2) and 7 missense mutations of unknown significance (11.7%), were found among the 60 patients. More than half of the mutation were novel, and were not reported in the database. Most of the BRCA-associated patients had no history of breast cancer. No treatment related failures were observed in the BRCA carriers, with the exception of one patientthat had experienced a new primary tumor of the contralateral breast. The seven year relapse free survival rate were 50 and 79% in the BRCA carrier and BRCA negative patients, respectively. Although the expression of estrogen and progesterone receptors were less common, and histological features more aggressive, in the BRCA associated tumors, the outcome of the patients with BRCA mutations was not poorer than that of the patients without deleterious mutations. CONCLUSION: Despite the BRCA mutation carriers having adverse prognostic features, the recurrence rate was relatively lower than that in the BRCA non-carrying Korean patients with early-onset breast carcinomas. In addition, although the prevalence of the BRCA mutation in Korean patients was higher than that in white patients, the penetrance of the cancer seemed to be relatively low in Korean women carrying BRCA mutations. A large population based study of the BRCA mutation, with a long-term follow-up of the study patients will be required to confirm these results.