Metastatic breast cancer with double heterozygosity for the BRCA1 and BRCA2 genes responding to olaparib: A case report.

Olaparib was the first poly ADP-ribose polymerase inhibitor approved for patients with cancer with mutations in either BRCA1 or BRCA2 in China. To the best of our knowledge, however, no study has described the efficacy of olaparib for patients with breast cancer with double mutations in BRCA1 and BRCA2. The present case report describes a patient with breast cancer with deleterious germline mutations in both BRCA1 and BRCA2. The 56-year-old patient with multiple metastatic breast cancer underwent breast cancer resection with 12 years interval between removal of the left and right breast. Germline mutations in both BRCA1 (S405X) and BRCA2 (W2990X) were identified by NGS. She received two cycles of chemotherapy with a combination of albumin-bound paclitaxel and capecitabine; the response was progressive disease. Subsequently, the patient was treated with a gradual dosage of decreasing olaparib (600 to 300 mg BID) for 6 months until grade 3 anemia could not be alleviated by giving erythropoietin and iron, and CT imaging showed a partial response (35% reduction). The patient then switched to exemestane therapy due to the continuous grade 3 anemia. In conclusion, the present study reported a female patient with double heterozygosity of BRCA1 and BRCA2 who benefited from olaparib monotherapy. Thus, olaparib may be a suitable treatment for such patients.

Potential Phytochemicals for Prevention of Familial Breast Cancer with BRCA Mutations.

Breast cancer has remained a global challenge and the second leading cause of cancer mortality in women and family history. Hereditary factors are some of the major risk factors associated with breast cancer. Out of total breast cancer cases, 5-10% account only for familial breast cancer, and nearly 50% of all hereditary breast cancer are due to BRCA1/BRCA2 germline mutations. BRCA1/2 mutations play an important role not only in determining the clinical prognosis of breast cancer but also in the survival curves. Since this risk factor is known, a significant amount of the healthcare burden can be reduced by taking preventive measures among people with a known history of familial breast cancer. There is increasing evidence that phytochemicals of nutrients and supplements help in the prevention and cure of BRCA-related cancers by different mechanisms such as limiting DNA damage, altering estrogen metabolism, or upregulating expression of the normal BRCA allele, and ultimately enhancing DNA repair. This manuscript reviews different approaches used to identify potential phytochemicals to mitigate the risk of familial breast cancer with BRCA mutations. The findings of this review can be extended for the prevention and cure of any BRCAmutated cancer after proper experimental and clinical validation of the data.

Prognostic and Predictive Biomarkers in Familial Breast Cancer.

Large numbers of breast cancers arise within a familial context, either with known inherited germline mutations largely within DNA repair genes, or with a strong family history of breast and/or ovarian cancer, with unknown genetic underlying mechanisms. These cancers appear to be different to sporadic cases, with earlier age of onset, increased multifocality and with association with specific breast cancer histological and phenotypic subtypes. Furthermore, tumours showing homologous recombination deficiency, due to loss of BRCA1, BRCA2, PALB2 and CHEK2 function, have been shown to be especially sensitive to platinum-based chemotherapeutics and PARP inhibition. While there is extensive research and data accrued on risk stratification and genetic predisposition, there are few data pertaining to relevant prognostic and predictive biomarkers within this breast cancer subgroup. The following is a review of such biomarkers in male and female familial breast cancer, although the data for the former are particularly sparse.

Hereditary breast cancer: syndromes, tumour pathology and molecular testing.

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes - TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz-Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low-penetrance breast cancer susceptibility alleles, is also a well-recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype-phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.

Does mainstream BRCA testing affect surgical decision-making in newly-diagnosed breast cancer patients?

BACKGROUND: Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making. METHODS: Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively. RESULTS: 580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38-57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy. CONCLUSION: Timely BRCA gene testing influences surgeons' and patients' choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk.

Ethnic predisposition, risk factors and breast cancer presentation; a 10-year data. Single centered prospective cohort study from Karachi.

Background: Breast cancer, a leading cause of mortality among females, has been the center of research for many decades. Work is in progress to advance the research worldwide and in our region. This study is conducted to look into regional ethical predilection/age, clinical presentation/stage, pathological subtypes and risk factors of BC among patients of Karachi, with the aim of proposing a ground in our policy making regarding protocol setting for screening and management of BC patients. Methods: A prospective cohort study started at public Hospital, Karachi from 2010 to 2020.500 females with histo-pathologically proven BC selected. History, clinical examination, radiological and histo-pathological data retrieved; data regarding age, ethnicity, family history, parity, marriage/menopause, stage/lump size/symptoms were filled on pro-forma. Primary outcomes were age, ethnicity, family history, stage/histological type and menopausal status of our cohort while secondary outcomes were parity, marriage, symptoms and lump size/site. Data analyzed using SPSS in ranges and percentages. Results: Among different ethnicities, Makrani were the most affected(34%). Majority were premenopausal females ≤50yrs (78%). Infiltrating ductal carcinoma (88.8%) was the commonest subtype. Family history was positive in few (5.8%). Parity and marital status had no effect on our population. Breast lump (88%) was the commonest presenting symptom and 51% of our patients had the right side involved. Upper outer quadrant (51%) was the most involved quadrant and the majority (46%) were stage II. Conclusions: Age of presentation is around a decade earlier in our region, with women of Makrani descent more prone to develop BC. 2/3rd of patients were premenopausal, with lump breast as primary complaint. Majority of patients presented in stage-II. Results of age and racial predilection in our population suggest us to concentrate future research more on genetic profiling so we incorporate the results to devise population specific protocols with reference to age, presentation, BC type, ethnicity & risk factors.Record submitted retrospectively at ClinicalTrials.govt on 09-07-2022 NCT05458570 .

A systematic review exploring the role of modern radiation for the treatment of Hereditary or Familial Breast Cancer.

The diagnosis of hereditary or familial breast cancers influences the locoregional approach to breast cancer, with most patients undergoing mastectomy to avoid or minimize the use of adjuvant radiation therapy. We evaluated the current literature about known high- and moderate-penetrance genes and studied their impact on local control, toxicities, and contralateral breast cancers after adjuvant radiation therapy. The aim is to encourage the safe use of adjuvant radiation therapy when indicated in concordance with the updated guidelines.

Prevalence of Cancer Predisposition Germline Variants in Male Breast Cancer Patients: Results of the German Consortium for Hereditary Breast and Ovarian Cancer.

Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54−26.82, p < 10−5; BRCA2: OR = 77.71, 95% CI = 58.71−102.33, p < 10−5). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59−7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02−36.02, p < 10−5; ATM: OR = 3.36, 95% CI = 0.89−8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.

Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study.

BACKGROUND: Precision oncology has been increasingly used in clinical practice and rapidly evolving in the oncology field. Thus, this study was performed to assess the frequency of germline mutations in early and late onset familial breast cancer (BC) Egyptian patients using multi-gene panel sequencing to better understand the contribution of the inherited germline mutations in BC predisposition. Moreover, to determine the actionable deleterious mutations associated with familial BC that might be used as biomarker for early cancer detection. METHODS: Whole blood samples were collected from 101 Egyptian patients selected for BC family history, in addition to 50 age-matched healthy controls. A QIAseq targeted DNA panel (human BC panel) was used to assess the frequency of germline mutations. RESULTS: A total of 58 patients (57.4%) out of 101 were found to have 27 deleterious germline mutations in 11 cancer susceptibility genes. Of them, 32 (31.6%) patients carried more than one pathogenic mutation and each one carried at least one pathogenic mutation. The major genes harboring the pathogenic mutations were: ATM, BRCA2, BRCA1, VHL, MSH6, APC, CHEK2, MSH2, MEN1, PALB2, and MUTYH. Thirty-one patients (30.6%) had BRCA2 mutations and twenty (19.8%) had BRCA1 mutations. Our results showed that exon 10 and exon 11 harbored 3 and 5 mutations, respectively, in BRCA1 and BRCA2 genes. Our analysis also revealed that the VHL gene significantly co-occurred with each of the BRCA2 gene (p = 0.003, event ratio 11/21), the MSH2 gene (p = 0.01, 4/10), the CHEK2 gene (p = 0.02, 4/11), and the MSH6 gene (p = 0.04, 4/12). In addition, the APC gene significantly co-occurred with the MSH2 gene (p = 0.01, 3/7). Furthermore, there was a significant mutually exclusive event between the APC gene and the ATM gene (p = 0.04, 1/36). Interestingly, we identified population specific germline mutations in genes showing potentials for targeted therapy to meet the need for incorporating precision oncology into clinical practice. For example, the mutations identified in the ATM, APC, and MSH2 genes. CONCLUSIONS: Multi-gene panel sequencing was used to detect the deleterious mutations associated with familial BC, which in turns mitigate the essential need for implementing next generation sequencing technologies in precision oncology to identify cancer predisposing genes. Moreover, identifying DNA repair gene mutations, with focus on non-BRCA genes, might serve as candidates for targeted therapy and will be increasingly used in precision oncology.

Familial Breast Cancer: Disease Related Gene Mutations and Screening Strategies for Chinese Population.

BACKGROUND: About 5%-10% of the breast cancer cases have a hereditary background, and this subset is referred to as familial breast cancer (FBC). In this review, we summarize the susceptibility genes and genetic syndromes associated with FBC and discuss the FBC screening and high-risk patient consulting strategies for the Chinese population. METHODS: We searched the PubMed database for articles published between January 2000 and August 2021. Finally, 380 pieces of literature addressing the genes and genetic syndromes related to FBC were included and reviewed. RESULTS: We identified 16 FBC-related genes and divided them into three types (high-, medium-, and low-penetrance) of genes according to their relative risk ratios. In addition, six genetic syndromes were found to be associated with FBC. We then summarized the currently available screening strategies for FBC and discussed those available for high-risk Chinese populations. CONCLUSION: Multiple gene mutations and genetic disorders are closely related to FBC. The National Comprehensive Cancer Network (NCCN) guidelines recommend corresponding screening strategies for these genetic diseases. However, such guidelines for the Chinese population are still lacking. For screening high-risk groups in the Chinese population, genetic testing is recommended after genetic counseling.

Gestational breast cancer in a patient with Crohn's disease: two case reports.

BACKGROUND: Diagnosis of breast cancer during gestation is a rare occurrence. In addition, the diagnosis of breast cancer in a patient with Crohn's disease is not common. We present a rare case of gestational breast cancer in a patient with Crohn's disease, with a concurrent breast cancer diagnosis in her sister. CASE PRESENTATION: A 31-year-old Syrian woman with Crohn's disease was diagnosed with breast cancer at 30 weeks gestation; she received neoadjuvant chemotherapy during gestation. Incidentally, her 37-year-old sister was also diagnosed concomitantly with breast cancer. Both sisters underwent and successfully completed surgery and adjuvant therapy. At a 5-year review, both patients showed no signs of recurrence. The Crohn's disease symptoms have also improved after chemotherapy, and the baby born after gestational chemotherapy is currently 5 years old with normal psychomotor development and without any congenital malformations. CONCLUSIONS: This case report highlights the impact of gestation on breast cancer outcomes, the possibility of giving chemotherapy during gestation, and the effect of chemotherapy on the symptoms of Crohn's disease.

The DAMA25 Study: Feasibility of a Lifestyle Intervention Programme for Cancer Risk Reduction in Young Italian Women with Breast Cancer Family History.

BACKGROUND: Diet and physical activity (PA) can modulate sporadic and possibly familial breast cancer (BC) risk. The DAMA25 study is a single-arm 12-month intervention aimed to modify dietary and PA habits in healthy young Italian women with a positive BC family history, categorized as having intermediate or high genetic risk according to NICE (National Institute for Health and Cancer Excellence) guidelines. METHODS: Participants, aged 25-49 years, were asked to adopt a diet mainly based on plant-based foods and to increase moderate daily activities combined with 1 h/week of more intense activity. Cooking lessons, collective walks, educational sessions, brochures, booklets and online materials were implemented. Dietary, PA habits and anthropometry were collected at baseline and at the end of the intervention. Changes on dietary, lifestyle habits and anthropometry were evaluated by GLM adjusted for weight reduction counselling aimed to participant with a BMI ≥ 25, age and baseline values of each variable. RESULTS: Out of 237 eligible women 107 (45.2%) agreed to participate and among them 98 (91.6%) completed the intervention. The adherence rate of the intervention was 77.8%. We observed a reduction in red and processed meat (p < 0.0001) and cakes consumption (p < 0.0001). Consumption of whole grain bread (p < 0.001), leafy vegetables (p = 0.01) and olive oil (p = 0.04) increased. We observed an increase in moderate (p < 0.0001) and more intense (p < 0.0001) recreational activities, an average 1.4 kg weight loss (p = 0.005), a reduction of waist circumference (p < 0.001) and fat mass (p = 0.015). CONCLUSIONS: The DAMA25 study shows that it is feasible an intervention to improve in the short-term dietary and PA habits and anthropometry in women with high BC familial risk.

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families.

OBJECTIVE: Approximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families. METHODS: Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families. RESULTS: Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05). CONCLUSIONS: In addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

Soluble interleukin-2 receptor as a predictive and prognostic marker for patients with familial breast cancer.

The incidence of breast cancer increases annually, and it has become common within families of breast cancer patients. Interleukin-2 activates cytotoxic T lymphocytes, which are important for cancer immunity. To identify markers of increased familial breast cancer risk, soluble interleukin-2 receptor levels and immunologic factors were investigated in familial breast cancer and non-familial breast cancer patients. Of 106 untreated breast cancer patients in this study, 24 had familial breast cancer and 82 had non-familial breast cancer. The patients' soluble interleukin-2 receptor, interleukin-10, vascular endothelial growth factor, interleukin-17, regulatory T cell, myeloid-derived suppressor cell, white blood cell, and C-reactive protein levels, and their neutrophil-to-lymphocyte ratios were measured, and their prognoses were compared according to the soluble interleukin-2 receptor levels. Additionally, postoperative tissues from the patients with high soluble interleukin-2 receptor levels were stained with programmed cell death ligand 1 and cluster of differentiation 8. The soluble interleukin-2 receptor level in the familial breast cancer patients was significantly higher, and it showed significantly stronger correlations with the neutrophil-to-lymphocyte ratio and the interleukin-10, vascular endothelial growth factor, interleukin-17, regulatory T cell, myeloid-derived suppressor cell, white blood cell, and C-reactive protein levels, than in the non-familial breast cancer patients. The regulatory T cell and myeloid-derived suppressor cell levels were significantly higher in the patients with high soluble interleukin-2 receptor levels, and the overall survival and disease-free-survival rates were significantly worse for the familial breast cancer patients than for the non-familial breast cancer patients. Triple-negative breast cancer tissues from the familial breast cancer patients with high soluble interleukin-2 receptor levels stained well for programmed cell death ligand 1 and cluster of differentiation 8. Soluble interleukin-2 receptor levels can be used to predict the prognosis of familial breast cancer patients. Prospectively identifying patients who are less likely to have non-familial breast cancer is vital for improving their overall survival.

Mutations in BRCA-related breast and ovarian cancer in the South African Indian population: A descriptive study.

Knowledge of the genetic landscape of a specific population group is vital for population-specific diagnosis and treatment of familial breast cancer. Although BRCA-related diagnostic testing has long been implemented in South Africa, the genotyping approach previously failed for the SA Indian population as it was based on other SA population groups. Because this population is uniquely admixed, the lack of population-specific data resulted in the implementation of comprehensive mutation screens for BRCA1/2. A total of 223 female patients were screened for clinically actionable variants. High-resolution melting analysis (HRMA) was used to screen 88 patients for DNA alterations in the coding and splice site boundaries of BRCA1 exons 2-9, BRCA1 exons 11-23, BRCA2 exons 2-9 and BRCA2 exons 12-27. The protein truncation test (PTT) was used to screen the three larger exons (BRCA1 exon 10 and BRCA2 exons 10 and 11) for protein termination changes. Multiplex ligation-dependent probe amplification (MLPA) was used to determine the presence of larger indels and possible copy number differences. Next Generation Sequencing (NGS) was performed on the remaining 135 samples. All potential variants were confirmed by performing Sanger DNA sequencing. The search revealed 28 different pathogenic heterozygotic variants, together with nine variants of unknown significance (VUS). The results suggested that the SA Indian population represents a different genetic admixture compared to that of mainland India, as only five pathogenic variants corresponded to those reported for mainland India. Familial breast cancer testing for SA Indian patients should therefore be performed as comprehensively as possible as the pathogenic variants seem to be family- rather than population-specific. Furthermore, predictive testing of family members will contribute to relieve the financial burden on the country's healthcare system, as increased surveillance and appropriate management could prevent disease.

Decision Aids for Preventive Treatment Alternatives for BRCA1/2 Mutation Carriers: a Systematic Review.

Introduction Women with a pathogenic BRCA1/2 mutation have a markedly increased lifetime risk of developing breast and/or ovarian cancer. The current preventive treatment alternatives that are offered are an intensified breast cancer screening programme and risk-reducing operations. Before deciding on one option, medical and personal factors such as life situation and individual preferences must be weighed carefully. Decision aids are used internationally to support BRCA1/2 mutation carriers during their decision-making process. In this study these are analysed structurally for the first time and their applicability to the German context is examined. Material and Methods A systematic literature search in five electronic databases and a manual search were performed. The identified decision aids were evaluated with regard to formal criteria, medical content and quality. The qualitative assessment used the criteria of the International Patient Decision Aid Standards Collaboration (IPDASi v4.0), which examined various dimensions (e.g., information, probabilities, values). Results Twenty decision aids, which were published between 2003 and 2019 in Australia (n = 4), the United Kingdom (n = 3), Canada (n = 2), the Netherlands (n = 2) and the USA (n = 9), were included. Nine focus on BRCA1/2 mutation carriers and eleven include other risk groups. Eighteen include risk-reducing operations as decision options, 14 list screening methods for breast and/or ovarian cancer, and 13 describe the possibility of pharmacological prevention by means of selective oestrogen receptor modulators or aromatase inhibitors. Nine of the 20 decision aids meet fundamental quality criteria (IPDASi v4.0 qualification criteria). Conclusion International decision aids can serve formally as a basis for a German decision aid for BRCA1/2 mutation carriers. Some of them differ markedly in content from the recommendations of German guidelines. Only a few achieve a high quality.

Multigene Panel Testing for Hereditary Cancer and Genetic Counseling.

As sequencing technology and information of the genomic causes for cancer development expand, multi-gene panel testing for hereditary cancer is increasing in clinical practice. In this chapter, we reviewed the application of multi-gene panel with pre-/post- testing considerations and summarized genetic counseling based on panel testing results in clinical field. In addition, we introduce multi-gene panel for hereditary cancer developed in Seoul National University Hospital.

The clinicopathological and MRI features of patients with BRCA1/2 mutations in familial breast cancer.

BACKGROUND: To determine the histopathological and MRI features of BRCA1/2 mutation-associated familial breast cancers compared with those of BRCA1/2 mutation-negative and sporadic breast cancers and to further compare the imaging features of cancers from BRCA1 and BRCA2 mutation carriers according to lesion type on MRI. METHODS: A retrospective review of medical records was conducted to determine tumour clinicopathologic features and MRI characteristics between June 2011 and July 2017, and 93 lesions with BRCA mutations, 93 lesions without BRCA mutations from familial breast cancers and 93 lesions from sporadic breast cancers were included. Histopathologic data, including immunohistochemistry findings and MRI data according to the BI-RADS lexicon, were reviewed. The association between MRI or histopathologic findings and BRCA mutations was analysed. RESULTS: BRCA-positive familial breast cancers had a higher number of IDCs with high nuclear grade and lymph node metastasis (all P<0.05), while the BRCA-negative group had a significantly lower Ki-67 index (P<0.001). BPE on MRI was found to be significantly lower for BRCA mutations of familial breast cancer (P=0.024). BRCA1 carriers tended to exhibit the triple-negative phenotype with a more benign shape and margin (P=0.006 and 0.019), whereas BRCA2 mutations were associated with the luminal phenotype and more malignant features. CONCLUSIONS: BRCA mutation carriers had a significantly higher number of IDCs with more aggressive cancer, and BRCA-negative cancers had low proliferation levels. Background features on MRI may help to identify BRCA status, while tumour characteristics can differentiate the BRCA1/2 mutation status, consistent with the differences in their clinicopathologic features.

Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers.

Cells are continuously subjected to DNA damaging agents. DNA damages are repaired by one of the many pathways guarding genomic integrity. When one or several DNA damage pathways are rendered inefficient, cells can accumulate mutations, which modify normal cellular pathways, favoring abnormal cell growth. This supports malignant transformation, which can occur when cells acquire resistance to cell cycle checkpoints, apoptosis, or growth inhibition signals. Mutations in genes involved in the repair of DNA double strand breaks (DSBs), such as BRCA1, BRCA2, or PALB2, significantly increase the risk of developing cancer of the breast, ovaries, pancreas, or prostate. Fortunately, the inability of these tumors to repair DNA breaks makes them sensitive to genotoxic chemotherapies, allowing for the development of therapies precisely tailored to individuals' genetic backgrounds. Unfortunately, as with many anti-cancer agents, drugs used to treat patients carrying a BRCA1 or BRCA2 mutation create a selective pressure, and over time tumors can become drug resistant. Here, we detail the cellular function of tumor suppressors essential in DNA damage repair pathways, present the mechanisms of action of inhibitors used to create synthetic lethality in BRCA carriers, and review the major molecular sources of drug resistance. Finally, we present examples of the many strategies being developed to circumvent drug resistance.

Gene- and pathway-level analyses of iCOGS variants highlight novel signaling pathways underlying familial breast cancer susceptibility.

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.