Mutations In Breast Cancer Patients Research Articles

Identification of PIK3CA aberrations associated with telomere length in breast cancer

PIK3CA (p110α) mutations are the most common alterations in the phosphoinositide 3-kinase (PI3K) pathway, affecting about 27% of breast cancer (BCa) patients. Telomeres play crucial roles in chromosomal maintenance and stability. This study investigated the correlations between telomere length and PIK3CA mutations in BCa patients and compared these findings with the patients' clinical parameters.HRM assay was used to identify the PIK3CA mutations in 89 patients. The mutations were confirmed by Sanger sequencing, and the telomere length was analysed using RT-PCR.Thirty patients were found with mutations in the PIK3CA gene. The frequency of the PIK3CA mutations was also high in the following BCa types: luminal B molecular type, IDC histologic type, T2 stage, node (0) status, ER (+) and PR (+). There was a significantly high frequency of PIK3CA exon 20 mutations in the grade 2 tumours (p = .0272) and a significantly high frequency of PIK3CA exon 9 mutations in the node (0) tumours (p = .0016). In contrast, the telomeres were longer in the tumour tissues than in the healthy tissues (p = .3622). Moreover, in the tumours with the PIK3CA mutations, the telomeres were significantly longer than in the tumours that did not carry any PIK3CA mutations (p = .0118). The telomere length was also significant in the node (0) status tumours (p = .0253).These results suggest that longer telomeres may be a risk factor for BCa. An association was found between PIK3CA mutations and longer telomere length in BCa. Telomere length and PIK3CA in BCa may be developed as potential prognostic or diagnostic biomarkers for BCa risk prediction.

Novel mutations in breast cancer patients from southwestern Colombia.

Breast cancer is the leading cause of death by cancer among women in less developed regions. In Colombia, few published studies have applied next-generation sequencing technologies to evaluate the genetic factors related to breast cancer. This study characterized the exome of three patients with breast cancer from southwestern Colombia to identify likely pathogenic or disease-related DNA sequence variants in tumor cells. For this, the exomes of three tumor tissue samples from patients with breast cancer were sequenced. The bioinformatics analysis identified two pathogenic variants in Fgfr4 and Nf1 genes, which are highly relevant for this type of cancer. Specifically, variant FGFR4-c.1162G>A predisposes individuals to a significantly accelerated progression of this pathology, while NF1-c.1915C>T negatively alters the encoded protein and should be further investigated to clarify the role of this variant in this neoplasia. Moreover, 27 novel likely pathogenic variants were found and 10 genes showed alterations of pathological interest. These results suggest that the novel variants reported here should be further studied to elucidate their role in breast cancer.

316P - Clinicopathologic features of BRCA mutated breast cancer patients: Hacettepe experience

BackgroundImpaired DNA damage response (DDR) mechanisms and subsequent genomic instability is associated with carcinogenic process itself, but it also results in sensitivity of tumor cells to certain drugs and can be exploited to treat cancer by inducing deadly mutations or mitotic catastrophe. As a result, BRCA1/2 testing is recommended for a group individuals with breast/ovarian cancer. MethodsIn this study, we retrospectively invesitigated clinicopathologic features of 303 breast cancer patients tested for BRCA 1/2 mutation in an oncology institute. NCCN recommendations are used to select patients to be tested for BRCA mutations. ResultsA total of 303 patients were analysed for BRCA 1/2 mutations. Median age of the patients at diagnoses were 40 (21-65). Family history for BRCA related cancers were detected in 120 patients (39.6%). BRCA 1/2 mutations have been shown in 98 of 303 patients (32.3%). Of 98 BRCA mutated patients, 43 had pathogenic BRCA1 mutation, 39 had pathogenic BRCA2 mutation, 11 had variant of uncertain significance (VUS) BRCA2 mutation, 3 had VUS BRCA1 mutation and 2 had pathogenic BRCA1 and 2 mutations. Molecular subtypes of tumors have been shown in Table.Table316P Molecular subtypes of tumorsTableBRCA StatusHR(+)/ HER2(-), N(%)HR(+)/ HER2(+), N(%)HR(-)/ HER2(+), N (%)Triple(-), N (%)N/A,N(%)BRCA118 (41.8%)2 (4.6%)022 (51.1%)1 (2.3%)BRCA225 (64.1%)3 (7.7%)06 (15.3%)5 (12.8%)BRCA1 VUS2 (66.7%)001 (33.3%)0BRCA2 VUS11 (100%)0000BRCA1+201 (50%)01 (50%)0BRCA mut (-)126 (61.4%)25 (12.1%)12 (5.8%)32 (15.6%)10 (4.8%)TOTAL182 (60%)31 (10.2%)12 (3.9%)62 (20.4%)16 (5.2%)Twelve of 98 BRCA mutated patients (12.2%) were de novo metastatic while 15 patients (15.3%) faced with metastatic disease during follow-up. In the BRCA mutated group there was significantly high rate of metastatic disease has been detected comparing BRCA non-mutated group (27.5% vs %16.5% respectively, p=0.026). Metastatic BRCA mutant patients showed worse OS numerically but data is not statistically significant (P=0.894). Nine patients were diagnosed with contralateral breast cancer, and 3 patients was diagnosed with BRCA-related cancers during follow-up. Prophylactic surgery (contralateral mastectomy and/or oophorectomy) was performed in 32 of 98 patients. ConclusionsAccording to this retrospective study, BRCA mutant patients tend to have worse clinical and pathological features comparing age-matched controls. Legal entity responsible for the studySercan Aksoy. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Novel PALB2 deleterious mutations in breast cancer patients from South Indian population

Breast cancer is the most common cancer in women across the world. Partner and localizer of BRCA2 (PALB2) were recently identified as a breast cancer predisposition gene. The ultimate goal of this study is to understand the status of PALB2 mutations among the breast cancer subjects from the Indian population. We have evaluated the PALB2 gene mutation in 200 breast cancer patients and 200 controls that tested negative for BRCA1/2. Single Stranded Conformation Polymorphism (SSCP) assay was performed for screening the variants on amplified regions followed by direct sequencing for conforming mutations. Among the analyzed subjects, 128 patients were of inherited familial history and the rest 72 patients were of sporadic cases. Two novel deleterious mutations and one novel missense mutation were identified from this study, with the prevalence of about 3.5% (7/200). Among the deleterious mutations in familial breast cancer, PALB2 c.780delG and c.725delT was identified. One missense mutation of PALB2 c.404C > T was found in our study subjects. In this study, the prevalence of PALB2 gene mutation in familial breast cancer is about 4.6% (6/128). Our study demonstrates that the PALB2 gene mutations prevail among familial breast cancer patients.Clinically, these data may be helpful in the genetic counseling for breast cancer patients with PALB2 germline mutation.

Functional polymorphism within miR-23a∼27a∼24-2 cluster confers clinical outcome of breast cancer in Pakistani cohort.

MicroRNAs (miRNAs) are small regulatory RNA molecules that control gene activity by base pairing with target messenger RNA leading to their cleavage or translational repression. Previous studies show an involvement of miRNAs in various diseases including cancer. Members of the Mir-23a cluster (MIR23A, MIR24-2and MIR27A) are involved in breast cancer (BC). In the present study, miR-23a/24-2/27a cluster was screened for genetic mutation in BC patients. Heterozygous (A/G allele) as well as homozygous (G/G allele) variants were found in mir-27a gene in screened BC patients. RNA structural analysis revealed that the single nucleotide polymorphism (SNP) effects the size of the terminal loop in the precursor miRNA (pre-miRNA). The altered (G allele) hairpin structure observed was two bases longer than the reference (A allele) hairpin.

Abstract OT3-03-03: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Methods: Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites. Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-03.

The distinct clinicopathological and prognostic implications of PIK3CA mutations in breast cancer patients from Central China.

PurposeThe mutation status and prognostic value of PIK3CA in breast cancer were widely investigated, which showed significant difference among the patients from vast areas around the world. In this study, the frequency, distribution, bias, and burden of PIK3CA mutations and their relationships with clinicopathologic variables and prognostic significances were investigated in the breast cancer patients from Central China.Materials and methodsSomatic mutations in exon 9 and exon 20 of PIK3CA gene were analyzed using Sanger sequencing combining with targeted next generation sequencing in 494 breast cancer patients from Central China. The correlations between PIK3CA mutations and clinicopathological characteristics and the prognostic values of multiple PIK3CA mutation statuses were evaluated.ResultsPIK3CA mutations were found in 38% of the patients and associated with estrogen receptor-positive, progesterone receptor-positive, low Ki67 labeling index, and luminal/human epidermal growth factor receptor 2-enriched subtypes. Meanwhile, the prognosis of the total patients and the patients in old diagnostic age, progesterone receptor-negative, low Ki67 labeling index, and luminal/human epidermal growth factor receptor 2-enriched subgroups was significantly related to PIK3CA mutations. Most interestingly, the distribution, bias, and burden of PIK3CA mutations were correlated with different clinical, pathological, and molecular features as well as distinct prognostic implications in multiple breast cancer subgroups.ConclusionThe frequency, distribution, bias, and burden of PIK3CA mutations were associated with various clinical, pathological, and molecular characteristics in the breast cancer patients from Central China. These different mutation statuses can be used as potential indicators of prognosis in multiple breast cancer subgroups.

Identification of BRCA1/2 mutations in breast cancer patients by next-generation sequencing

Breast cancer is one of the most widespread forms of solid tumors. By analyzing the traits of breast cancer pathogenesis at the molecular level using modern genetic analysis techniques and at different stages of the disease new data can be obtained to be further utilized in clinical practice. Molecular profiling based on next-generation sequencing is being increasingly applied as a clinical test to select target drugs for treating breast cancer patients with tumors highly resistant to therapy. In this study, we performed targeted sequencing of BRCA1 and BRCA2 oncogenes. In the total of 66 DNA samples from patients with breast tumors, BRCA1/2 mutations were found in 39 patients. There were 78 unique genetic variants, including 30 mutations in BRCA1 and 48 mutations in BRCA2. We identified 33 mutations affecting the sites of post-translational modification in proteins (PMT mutations).

Identification of BRCA1/2 mutations in breast cancer patients by next-generation sequencing

Рак молочной железы (РМЖ) является одной из наиболее распространенных форм солидных опухолей. Анализ особенностей патогенеза РМЖ на молекулярном уровне с применением современных методов генетического анализа и на разных стадиях заболевания позволяет получить новые данные для их дальнейшего применения в клинической практике. Молекулярное профилирование с применением технологий высокопроизводительного секвенирования все чаще применяют в качестве клинического теста при подборе таргетных препаратов для лечения пациентов с высокорезистентными к терапии опухолями при РМЖ. Целью работы было провести таргетное секвенирование генов BRCA1 и BRCA2 в составе панели онкогенов. Из 66 образцов ДНК пациентов с опухолями молочной железы, мутации BRCA1/2 обнаружены у 39 пацентов. Найдено 78 уникальных генетических вариантов, из них 30 мутаций в гене BRCA1 и 48 мутаций в гене BRCA2. Идентифицировано 33 мутации, оказывающие влияние на сайты посттрансляционной модификации белков (PMT-мутации).

BRCA1 mutation in breast cancer patients: Analysis of prognostic factors and survival.

The presence of BRCA1 mutations is associated with an increased risk of breast and ovarian cancer. The present study compared clinicopathological characteristics and overall survival (OS) of hereditary and sporadic breast cancer. Using data collected from a previous study conducted between 2007-2016 at the Maria Skłodowska Curie Cancer Center and Institute of Oncology (Gliwice, Poland), the prognostic factors and survival in 60 breast cancer mutation carriers were analyzed. A control group was selected from the breast cancer patients without BRCA mutations (n=386). BRCA mutation carriers had significantly worse survival when compared with non-carriers (P=0.017). The 10-year OS rate was 78.0% for all analyzed groups: 65.9% for BRCA mutation carriers and 81.1% for non-carriers. In the univariate analyses, BRCA mutation carriers had a significantly higher risk of mortality in comparison to non-carriers [hazard ratio (HR)=1.87; 95% confidence interval (CI) 1.08-3.25]. Increased tumor size (HR=3.64), lymph node metastases (HR=2.45) and higher histological grade (HR=2.84) were significant factors for worse OS. Positive estrogen receptor status was associated with a better OS (HR=0.49, P=0.022). Age ≤40 years (HR=0.48, P=0.081) was an insignificantly favorable factor. The 10-year survival rate was significantly decreased in patients with BRCA1 mutation. Therefore, negative factors for OS in mutation carriers included lymph nodes metastases, negative steroid receptor status and increased tumor size.

Subtypes in BRCA-mutated breast cancer

Approximately 3% to 5% of breast cancer patients are BRCA1 or BRCA2 germline mutation carriers. In this study, we correlated the distribution of intrinsic molecular subtypes according to failure pattern in a Danish cohort of BRCA germline–mutated breast cancer patients. Tumor tissues from 425 BRCA germline–mutated breast cancer patients were analyzed by immunohistochemistry for hormone receptor status, proliferation index (Ki-67), and HER2. Surrogate intrinsic molecular subtypes were assigned according to approximated St Gallen criteria. Annual hazard rates (AHR) were calculated for death and local or distant relapse, contralateral breast cancer, new primary cancer other than breast cancer, or death as first event (disease-free event). Luminal A–like subtype was observed with a frequency of 9% and 35% for BRCA1 and BRCA2, respectively, and for both BRCA1 and BRCA2 patients, the luminal B–like subtype was more frequent than the luminal A–like subtype (BRCA1 21% and BRCA2 40% luminal B–like). No events or deaths were observed for luminal A–like subtype during the first 2.5 and 0 to 5 years, respectively. AHRs for luminal B–like tumors were 5.34% (95% confidence interval [CI], 1.49-1.19) and 1.76% (95% CI, 0.36-3.16) for disease-free event and death, respectively, and those for basal-like were 6.58% (95% CI, 2.98-10.18) and 4.54% (95% CI, 2.69-6.40). A substantial proportion of BRCA carriers had luminal A–like subtype, and these were mainly BRCA2 carriers. Luminal A–like subtype was significantly associated with low AHR the first 5 years after surgery. This study warrants further exploration of the impact of the molecular intrinsic subtypes on survival in BRCA-mutated breast cancer patients.

Intratumor heterogeneity ofHMCN1mutant alleles associated with poor prognosis in patients with breast cancer

Human breast cancers comprise a complex and highly heterogeneous population of tumor cells. Intratumor heterogeneity is an underlying cause of resistance to effective therapies and disease recurrence. To explore prognostic factors based on intratumor heterogeneity, we analyzed genomic mutations in breast cancer patients registered in The Cancer Genome Atlas. We calculated the variant allele frequency (VAF) at each mutation site and evaluated the associations of VAFs with the prognosis of breast cancer. VAFs of HMCN1 correlated with the prognosis and lymph node status. Although the detailed function of HMCN1 remains unknown, it is located in extracellular matrix and the mutation in the gene might be associated with cancer cell invasion and metastasis. This finding suggests that HMCN1 is a potential metastatic factor and can be a candidate gene for targeted breast cancer therapy.

BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management.

BRCA1/2 mutations are involved in breast cancer (BC) susceptibility but their influence on outcome is unclear. We reviewed BC patients tested for BRCA to determine biological features and influence on outcome. BRCA-1 was correlated to younger age (P=0.035), nodal involvement (P=0.030), higher tumor grade (P=0.0022) and Ki-67 (P=0.014), ER/PgR negative status (P=0.00042 and 0.0091, respectively), and use of adjuvant chemotherapy (P=0.000038); BRCA was neither predictive for chemotherapy administration nor resulted in impaired outcome or occurrence of secondary BC. BRCA status did not influence outcome despite higher biological aggressiveness and younger age at presentation.

Inherited mutations in breast cancer patients with and without multiple primary cancers.

1503Background: Women with breast cancer have a 5-12% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primar...

PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.

PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.

Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients.

In this study, we evaluated the incidence of pathogenic germline mutations in 30 breast cancer susceptibility genes in breast cancer patients. Our aim was to understand the involvement of the inherited mutations in these genes in a breast cancer cohort. Two hundred ninety-six female breast cancer patients including 4.5% of familial breast cancer cases were included in the study. 200ng of genomic DNA was used to evaluate the pathogenic mutations, detected using Global Screening Array (GSA) microchip (Illumina Inc.) according to the manufacturer's instructions. The pathogenic frameshift and nonsense mutations were observed in BRCA2 (10.9%), MLH1 (58.6%), MTHFR (50%), MSH2 (14.2%), and CYTB (52%) genes. Familial breast cancer patients (4.5%) had variations in BRCA2, MLH1, MSH2, and CYTB genes. 28% of patients with metastasis, recurrence, and death harbored mono/biallelic alterations in MSH2, MLH1, and BRCA2 genes. The results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations, from Malwa region of Punjab. The screening of MSH2, MLH1, and BRCA2 should be carried in individuals with or without family history of breast cancer as these genes have been reported to increase the cancer risk by tenfold.

Triple negative breast cancer: new therapeutic approaches and BRCA status.

Treatment of triple negative breast cancer (TNBC) is a clinically challenging problem due to intriguing clinical and pathologic features of TNBC and natural or induced resistance to existing therapies. However, a great understanding of features of TNBC particularly associated with BRCA mutations has led to the development of different therapeutic approaches. Besides, identification of TNBC subtypes contribute to investigation of the underlying molecular differences and development of new strategies for the treatment of TNBC patients. In this review, we discussed the definition and characteristic properties of TNBC. We summarized an up-to-date description of the reported clinical trials of novel targeted strategies especially PARP inhibitors (PARPi) due to novel and highly potent for the treatment of TNBC. Additionally, we reviewed published studies which investigated the prevalence and types of BRCA1/2 mutation in breast cancer patients to assess and draw attention of association of BRCA status with TNBC. Consequently, the definition subtype of TNBC has important predictive value for the development of new therapeutic agents in the treatment of TNBC. Additionally, the incidence and types of mutations in BRCA-related pathways may be affected by ethnic origin and contribute to the risk of developing TNBC.

Multicenter cross-sectional screening of the BRCA gene for Chinese high hereditary risk breast cancer populations.

Due to lack of systematic reviews, BRCA, DNA Repair Associated (BRCA) mutations in the Chinese population are not completely understood. The following study investigates the prevalence and type of BRCA mutations in Chinese patients with high hereditary risk of breast cancer (BC). Patients Drwere recruited from 14 cities between October 2015 and February 2016, and were selected based on family and personal medical history. BRCA mutations were analyzed by collecting blood samples from all participants. 437 BC patients were included. A total of seventy-six (17.4%) mutation carriers were identified with no geographic difference. The mutation rate in the early-onset BC patients was lower compared to family history of breast/ovarian cancer (OC), bilateral BC, male BC, BC&OC or meeting ≥2 criteria (9.2 vs. 21.7, 24.0, 22.2, 16.7 and 24.3%, respectively, P=0.007). A total of 61 mutation sites were identified (BRCA1 32, BRCA2 29) including 47.5% novel sites and extra 10 variants of uncertain significance. A total of five sites were repeated in more than one unrelated patient. A total of 11 sites were associated with hereditary breast and ovarian cancer syndrome, two of which were confirmed by family pedigrees. Compared with BRCA- patients, patients with BRCA1 mutation tended to be triple-negative BC (P<0.001), whereas patients with BRCA2 mutation were more likely to be hormone receptor positive BC (P=0.02). The present study provides a general BRCA mutation profile in the Chinese population. The prevalence of BRCA mutation in BC patients with high hereditary risk is lower compared with Western populations. Chinese mutation type is different with Western people, without obvious founder mutation.

Abstract OT3-04-03: PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3 stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 Safety: both research arms combined. Stage 2 Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pickthewinner” design with 53 patients in each research arm. This allows a 90% power, 5% onesided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 Efficacy:anticipated pCR ˜55-60% for all trial patients and ˜60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 56 Sites activated: 15 [expected number of sites 30-50]. Citation Format: Abraham J, Vallier A-L, Qian W, Grybowicz L, Thomas S, Machin A, Harvey C, Chiu E, McAdam K, Hughes-Davies L, Roylance R, Copson E, Armstrong A, Provenzano E, Tischkowitz M, McMurtry E, Earl H. PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-04-03.

BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia.

We aimed to establish the spectrum of BRCA1/2 mutations among the breast cancer (BC) patients from the Republic of Macedonia. We used targeted next-generation sequencing (NGS), Sanger DNA sequencing, and multiplex ligation probe amplification analysis (MLPA) to search for point mutations and deletions/duplications involving BRCA1 and BRCA2-coding regions. We have analyzed a total of 313 BC patients, enriched for family history of cancer, early age of onset and bilateral and/or triple negative (TN) BC. A total of 26 pathogenic mutations were observed in 49 unrelated BC patients (49/313, 15.7%). BRCA2 mutations (27/49, 55.1%) were more common than BRCA1 mutations (22/49, 44.9%). We identified five novel point mutations, one in BRCA1 (c.4352_4356delA) and four in BRCA2 (c.151G>T, c.4707_4708delCA, c.7811_7814delTGTG, and c.9304_9305delG), as well as two novel deletions involving parts of the BRCA1 gene (c.81-?_593+?del and c.5470-?_5530+?del). The most common mutations were c.181T>G, c.5266dupC, and c.3700_3704del5 in BRCA1 and c.7879A>T, c.8317_8330del14 and c.5722_5723delCT in BRCA2 gene. Thus far, BRCA2 c.7879A>T and c.8317_8330del14 mutations have been described in several isolated cases; however, our study is the first one showing that they have a founder effect among Macedonian population. Nine recurrent mutations account for 65.3% of all of the detected mutations allowing for implementation of a fast first-step BRCA1/2 mutational screening strategy in our country. This study provides a comprehensive view of known and novel BRCA1/2 mutations in BC patients from the Republic of Macedonia and contributes to the global spectrum of BRCA1/2 mutations in breast cancer.