BRCA Mutation-associated Breast Cancer Research Articles

Perspectives and possibilities of preserving reproductive function in patients receiving antitumor treatment. Clinical observation

Currently, treatment of patients with early primary operable BRCA mutation-associated breast cancer requires integrative approach. A mutation in BRCA1/2 genes is a prognostically unfavorable factor increasing the risk of cancer of the contralateral breast, as well as ovaries, pancreas, fallopian tubes, and primary peritoneal cancer. In this clinical observation, an integrative multidisciplinary approach to treatment of a young patient with luminal B breast cancer is described which allowed to preserve the patient’s fertility and achieve pregnancy using assisted reproductive technologies.High effectiveness of the chosen treatment tactics in the framework of integrative approach in a specialized medical facility with experience in treatment of oncological diseases and preservation of reproductive function confirmed by clinical data and results of laboratory and instrumental exams is demonstrated.

Triple Negative Breast Cancer: Tumour Biology and Optimisation of Clinical Outcome

Triple negative breast cancer are breast cancer types that are difficult to treat because they lack expression of the estrogen receptor (ER), progesterone receptor (PR) and Human Epidermal Receptor 2 (HER2) gene amplification. Intensive research, analysis by the Cancer Genome Atlas (TCGA) Research Network and the advent of high-throughput technology tools has expanded the classification of TNBC tumors into subgroups according to its gene expression profiles in order to identify the different molecular subtypes, novel TNBC biomarkers that can play both predictive and prognostic roles and enhance therapeutic strategies. The “immune-activated,” subtype or tumours with defective BRCA pathway are amongst initial TNBC group with established genetic vulnerabilities that has allowed the addition of promising therapeutic approaches, including DNA-damaging agents (PARP inhibitors, platinum) as well as immunotherapy. The treatment of metastatic NBC (mTNBC) is currently transforming rapidly with better outcomes observed in clinical trials. The recent success with immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor 1 and programmed death ligand 1 (PD-L1) and PARP inhibitors for germline BRCA mutation-associated breast cancers as well as other novel strategies in mTNBC treatment will change the course of this unique cancer subtype in the future.

Effect and Safety of Therapeutic Regimens for Patients With Germline BRCA Mutation-Associated Breast Cancer: A Network Meta-Analysis

PurposeBreast cancer type 1 susceptibility (BRCA) mutations not only increase breast cancer (BC) risk but also result in poor survival and prognosis for BC patients. This study will analyze the effect and safety of therapeutic regimens for the treatment of BC patients with germline BRCA (gBRCA) mutations by network meta-analysis.MethodsPublic databases were searched from inception to 29 April 2021. Frequentist network meta-analysis was conducted to analyze the benefit of chemotherapy and targeted drug-related strategies.ResultsSeventeen articles were included in the analysis. For progression-free survival (PFS), olaparib (hazard ratio (HR): 0.58; 95% confidence interval (CI): 0.43 – 0.79), platinum (HR: 0.45; 95% CI: 0.22 – 0.89), and talazoparib (HR: 0.54; 95% CI: 0.41 – 0.71) were significantly better than platinum-free chemotherapy (Chemo). The results based on indirect comparisons showed that veliparib (Vel) + platinum + Chemo was also significantly better than Chemo (HR: 0.37; 95% CI: 0.20 – 0.69). For overall survival (OS), olaparib was significantly better than Chemo only in the population who did not receive prior chemotherapy. For pathologic complete response (pCR), bevacizumab+Chemo had a significant advantage over platinum agents (OR: 3.64; 95% CI: 1.07 - 12.39). Olaparib and talazoparib both showed significantly higher objective response rates (ORRs) than Chemo.ConclusionThe PFS results suggested that olaparib, talazoparib, and Vel+platinum agent+Chemo were ideal regimens for overall, TNBC, and advanced BC patients with gBRCA mutations. Whether PARPis are suitable for patients with gBRCA mutations who have received prior platinum therapy still needs to be clarified.

A review of current progress in triple-negative breast cancer therapy.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype known for its extremely high drug resistance, progression, poor prognosis, and lack of clear therapeutic targets. Researchers are aiming to advance TNBC treatment worldwide. In the past 2–3 years, more positive results have emerged in the clinical research on TNBC treatment. Based on the results, several impressive drugs have been approved to benefit patients with TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation-associated breast cancer (gBRCAm-BC) and immunotherapy using the checkpoint inhibitor atezolizumab in combination with nab-paclitaxel for programmed cell death-ligand 1-positive (PD-L1+) advanced TNBC. Although neoadjuvant therapy has focused on combinations of systemic agents to optimize pathologically complete response, metastatic TNBC still has a poor prognosis. Innovative multidrug combination systemic therapies based on neoadjuvants and adjuvants have led to significant improvements in outcomes, particularly over the past decade.

Targeted Therapies for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Until recently the backbone of therapy against TNBC has been cytotoxic chemotherapy. However, the breast oncology community is now seeing encouraging clinical activity from molecularly targeted approaches to TNBC. Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC. Improved biomarkers are needed to inform better patient selection for treatment with checkpoint inhibition. Higher response rates are seen when checkpoint inhibitors are combined with chemotherapy in the first-line setting and the use of these agents at an earlier stage of the disease does show promise. Antibody-drug conjugates are generating much excitement and may allow re-examination of prior cytotoxics that failed in development due to toxicity. Tumor sequencing is identifying potential molecular targets and ongoing studies are evaluating novel small molecule agents in this field such as AKT inhibition and many others. The treatment paradigm of chemotherapy as "one size fits all" approach for management of TNBC is changing based on molecular subtyping. Soon, the term TNBC may no longer be appropriate, as this heterogenous subtype of breast cancer is further refined by its molecular characteristics and clinical response to a targeted therapeutic approach.

SYK expression level distinguishes control from BRCA1-mutated lymphocytes.

BackgroundAbout 5%–10% of breast cancer and 10%–15% of ovarian cancer are hereditary. BRCA1 and BRCA2 are the most common germline mutations found in both inherited breast and ovarian cancers. Once these mutations are identified and classified, a course of action to reduce the risk of developing either ovarian or breast cancer – including surveillance and surgery – is carried out.PurposeThe purpose of the current research is to characterize the gene expression differences between healthy cells harboring a mutation in BRCA1/2 genes and normal cells. This will allow detection of candidate genes and help identify women who carry functional BRCA1/2 mutations, which cannot always be detected by the available sequencing methods, for example, carriers of mutations found in regulatory sequences of the genes.Materials and methodsOur cohort consisted of 50 healthy women, of whom 24 were individuals with BRCA1 or BRCA2 heterozygous mutations and 26 were non-carrier controls. RNA purified from non-irradiated lymphocytes of nine BRCA1/2 mutation carriers versus four control mutation-negative individuals was utilized for RNA-Seq analysis. The selected RNA-Seq transcripts were validated, and the levels of spleen tyrosine kinase (SYK) mRNA were measured by using real-time quantitative polymerase chain reaction.ResultsDifferences in gene expression were found when comparing untreated lymphocytes of BRCA1/2 mutation carriers and controls. Among others, the SYK gene was identified as being differently expressed for BRCA1/2 mutation carriers. The expression level of SYK was significantly higher in untreated healthy lymphocytes of BRCA1 heterozygote carriers compared with controls, regardless of irradiation. In contrast to normal tissues, in cancerous breast tissues, the expression levels of the BRCA1 and SYK genes were not intercorrelated.ConclusionCollectively, our observations demonstrate that SYK may prove to be a good candidate for better diagnosis, treatment, and prevention of BRCA1 mutation-associated breast cancer.

BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters?

Background: BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes. Methods: Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression. Results: In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24^low/CD44^high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively). Conclusions: There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.

Abstract 33: Mammary gland-specific deletion of Sirt1 delays mammary tumor growth and progression

Abstract SIRT1, a type III HDAC, is involved in regulation of several cellular processes including longevity, inflammatory response, energy metabolism and stem cell maintenance. SIRT1 first emerged as a potential anti-aging factor but now it is implicated in a number of age-related diseases including carcinogenesis and also in cancer stem cell maintenance. SIRT1 is over-expressed and/or catalytically activated in a variety of human cancers, including breast cancer. Several lines of evidence suggest that SIRT1 plays an important role in the activation of oncogenic signalling in mammary epithelial cells and that inhibition of SIRT1 has a direct effect on tumor cell growth and apoptosis. Despite the fact that SIRT1 is mainly involved in the promotion of oncogenic signaling, it can also function as a tumor suppressor via deacetylation and subsequent destabilization of various oncoproteins such as c-Myc, β-catenin, NF-κB, and HIF1α. Further, SIRT1 activation by resveratrol protects BRCA1 mutation-associated breast cancer. Thus, the precise role of SIRT1 in cancer is still unclear and remains debatable; it is likely that SIRT1 function in cancer is tissue/context-dependent. Therefore, understanding the precise role of SIRT1 in mammary tumorigenesis is essential for the rational design of SIRT1-based novel therapeutic drugs to combat breast cancer. To understand the functional implications of SIRT1 in breast cancer, we generated mammary gland-specific Sirt1-conditional knockout mice. Sirt1 deletion is associated with reduced mammary gland outgrowth and terminal end bud development, leading to significant reduction in mammary stem and progenitor cell formation. This perturbed mammary gland outgrowth and reduced mammary stem and progenitor cell formation recovers either by puberty or by exogenous administration of estrogen, suggesting that Sirt1 plays a key role in mediating estrogen signalling in mammary gland. To assess the functional role of SIRT1 in mammary tumor growth and progression, we crossed Sirt1-knockout mice with MMTV-PyMT-Tg mice and C3(1)-SV40-Tg mice, two spontaneous murine mammary tumor models. Sirt1 deletion significantly reduces the development and growth of spontaneous mammary tumors in both mouse models. This phenomenon is associated with significant reduction in cancer stem cell (CSC) formation with dramatic reduction in CSC markers Slug and Sox2 expression. We also found that Sirt1 deletion reactivates tumor suppressor proteins p53 and Foxo3a. In conclusion, our study provides direct evidence that SIRT1 plays a key role in breast cancer growth and progression by maintaining cancer stem cells via stabilization of CSC drivers and inactivation of tumor suppressors in mammary gland. Thus, pharmacological agents targeted to disrupt SIRT1 function and signalling might have potential in breast cancer treatment. Citation Format: Sabarish Ramachandran, Rajneesh Pathania, Selvakumar Elangovan, Ganapathy Vadivel, Muthusamy Thangaraju. Mammary gland-specific deletion of Sirt1 delays mammary tumor growth and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 33. doi:10.1158/1538-7445.AM2015-33

Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.

BackgroundOne of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.Materials and MethodsWe used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward’s hierarchical clustering method was used to classify the methylation status of the X chromosome.ResultsWe grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1–2.5, two copies of active X group: HR 1.4, 95% CI 1.0–1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI.ConclusionsLoss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness.

The PPARγ Agonist Efatutazone Increases the Spectrum of Well-Differentiated Mammary Cancer Subtypes Initiated by Loss of Full-Length BRCA1 in Association with TP53 Haploinsufficiency

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have anticancer activity and influence cell differentiation. We examined the impact of the selective PPARγ agonist efatutazone on mammary cancer pathogenesis in a mouse model of BRCA1 mutation. Mice with conditional loss of full-length BRCA1 targeted to mammary epithelial cells in association with germline TP53 insufficiency were treated with efatutazone through the diet starting at age 4 months and were euthanized at age 12months or when palpable tumor reached 1 cm(3). Although treatment did not reduce percentage of mice developing invasive cancer, it significantly reduced prevalence of noninvasive cancer and total number of cancers per mouse and increased prevalence of well-differentiated cancer subtypes not usually seen in this mouse model. Invasive cancers from controls were uniformly estrogen receptor α negative and undifferentiated, whereas well-differentiated estrogen receptor α-positive papillary invasive cancers appeared in efatutazone-treated mice. Expression levels of phosphorylated AKT and CDK6 were significantly reduced in the cancers developing in efatutazone-treated mice. Efatutazone treatment reduced rates of mammary epithelial cell proliferation and development of hyperplastic alveolar nodules and increased expression levels of the PPARγ target genes Adfp, Fabp4, and Pdhk4 in preneoplastic mammary tissue. Intervention efatutazone treatment in mice with BRCA1 deficiency altered mammary cancer development by promoting development of differentiated invasive cancer and reducing prevalence of noninvasive cancer and preneoplastic disease.

Diagnostic and Therapeutic Implications of Tumor-Infiltrating Lymphocytes in Breast Cancer

In the age of personalized medicine, the multitude of scientific publications describing new biomarkers has raised a lot of criticism, as many of these results have been rather difficult to validate. As a consequence to this criticism, we are observing a considerable improvement in the design of clinical biomarker studies, which are increasingly based on large sample cohorts from clinical trials. The article by Loi et al that accompanies this editorial exemplifies this. Loi et al report a prognostic role for tumor-associated lymphocytes in triple-negative breast cancer in a large prospective clinical trial, evaluating more than 2,000 tumor samples from patients with nodepositive breast cancer treated within the Breast International Group (BIG) 02-98 trial. The main finding of the study was that in estrogen receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative breast cancer (n 256) an increased lymphocytic infiltrate was linked to a reduced relapse rate and improved survival. This association was independent of the type of chemotherapy and was not observed in hormone receptor–positive tumors (n 1,078). In the subgroup of HER2-positive tumors (n 297) there was a significant interaction with benefit from anthracycline-only chemotherapy. It should be noted, however, that trastuzumab was not part of the adjuvant treatment in BIG 2 to 98, which limits the interpretationof theresults intheHER2-positivesubset inthecontextofcurrent therapeutic approaches. The study by Loi et al shows that tumor-infiltrating lymphocytes can be evaluated as a distinctive histological parameter using the predefined standardized definitions of intratumoral lymphocytes, stromal lymphocytes and lymphocyte-predominant breast cancer (LPBC). We have evaluated the nearly identical parameters in tumor samples from the neoadjuvant GeparTrio study, with a slightly different definition of LPBC. In this study, we have shown that a pretherapeutic immunological infiltrate is a predictive factor for response to neoadjuvant therapy. In the neoadjuvant situation, an increased rate of pathological complete response was observed in different tumor subtypes including hormone receptor–positive tumors. In contrast, the survival effect in the study by Loi et al was present only in the triple-negative subgroup. This difference could be explained by the fact that pathological complete remission is a surrogate end point for survival for triple-negative, but not for hormone receptor–positive breast cancer. The results of this report are consistent with the functional model that is emerging from preclinical studies. Zitvogel et al has evaluated the interaction between tumor cells and the immune system in various cellular and animal models. From their research the concept is emerging that the response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. In a recent paper, it has been shown that in particular those cancer cells that are hyperploid become immunogenic due to an increased accumulation of calreticulin on the cell surface. Those results from preclinical models as well as translational studies suggest that the combination of standard chemotherapy with immunomodulatory concepts might be worth an evaluation in clinical trials. It should be noted that a similar prognostic effect of increased lymphocytic infiltrate in triple-negative tumors has been observed in another study by West et al using immunohistochemistry as well as gene expression analysis of inflammatory markers. Molecular immunological parameters, such as immunoglobulin kappa C and IL8 have been reported as prognostic parameters in breast cancer, suggesting that those parameters could form a basis for future molecular diagnostic tests. From a pathologist’s point of view, the concept of a tumor that has a predominant lymphocytic infiltrate is similar to the classical tumor type of medullary breast cancer that has been described by Moore and Foote already in 1949. In classical pathology several definitions for medullary breast cancer have been suggested including parameters such as a predominant lymphocytic infiltrate, a so-called syncytial cell architecture and a well-defined border of the tumor. It has been shown that this tumor type has a particularly good prognosis. However, true medullary carcinoma is extremely rare, a recent evaluation of 12,409 patients from International Breast Cancer Study Group trials has found only 127 medullary carcinomas (1%). In addition to medullary breast cancer, a prominent lymphoplasmacellular infiltrate is observed in certain types of hereditary breast cancer. Evaluation of tumor-associated lymphocytes by standard hematoxylin and eosin staining is extremely inexpensive and can be performed easily in the setting of the routine histopathological evaluation. Considering that medullary breast cancer is an old pathology concept and that tumor-associated lymphocytes are also relevant for BRCA-mutation–associated breast cancer, pathologists should perhaps get used to reporting this parameter as a part of the standard histological description of breast cancer. In addition, the parameters of stromal and intratumoral infiltrate should be added to the standard parameters evaluated in the context of clinical studies. This is already JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 7 MARCH 2013

Systemic therapy options in BRCA mutation-associated breast cancer

BRCA mutation-associated breast cancers are characterized by deficient homologous recombination of DNA, and 80 % of BRCA1-associated breast cancers display the basal-like molecular subtype. Traditionally, BRCA carriers have received conventional systemic chemotherapy based on their baseline tumor characteristics, and it is generally accepted that after the appropriate treatment the prognosis of a mutation carrier is equivalent to that of a patient with sporadic breast cancer. However, with the growing understanding of the functions of BRCA1/2 proteins in homologous DNA repair, it is recognized that BRCA-associated breast cancer tumors may have distinct biochemical characteristics and thus require tailored treatment strategies. Tumors arising in patients with BRCA mutations were shown to be particularly sensitive to platinum compounds or inhibitors of poly(ADP-ribose) polymerase. In addition, BRCA1-mutation carriers seem to benefit from anthracycline-taxane-containing regimens as much as sporadic triple-negative breast cancers do. In this article, we review the functions of the BRCA1 and BRCA2 genes, and their differential chemosensitivity in both the preclinical and clinical settings. The optimal chemotherapy regimen for this subset of patients still remains to be determined.

Management of women with BRCA1 / 2 mutation-associated breast cancer

SUMMARY BRCA mutation-associated breast cancer differs from sporadic breast cancer as studies show that mutation carriers have a higher risk of breast and ovarian cancer, and also have differential sensitivity to chemotherapeutic agents. With the more readily available BRCA genetic testing, BRCA mutation status should be considered in high-risk women, including women who are diagnosed with breast cancer at an early age, have a strong family history or have tumors with triple-negative status. This article reviews the risk-reducing surgeries, including the prophylactic contralateral mastectomy and bilateral salpingo-oophorectomy, in women diagnosed with BRCA-associated breast cancer. Additionally, the sensitivity of BRCA-defective breast cancer cell lines to platinum cytotoxic compounds, PARP and endocrine therapy is reviewed.

P1-17-04: Phase I Study of PARP Inhibitor ABT-888 (Veliparib) in Combination with Cisplatin and Vinorelbine for Patients with Advanced Triple Negative Breast Cancer and/or BRCA-Mutation Associated Breast Cancer.

Abstract Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) have shown preclinical and clinical activity in targeting tumors with pre-existing DNA repair defects, in particular BRCA1 and BRCA2 deficient tumors. Cisplatin (CP) has demonstrated synergy with ABT-888 (veliparib) in breast cancer xenograft models and has anti-tumor activity in triple negative (TN) and BRCA-1 deficient breast cancer. Vinorelbine (V) combined with CP has shown safety and efficacy in patients with pretreated metastatic breast cancer. Methods: We are conducting a phase I study to determine the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic profiles (PD), and preliminary anti-tumor activity of veliparib in combination with CP and V in patients (pts) with metastatic breast cancer who are either TN or who have BRCA1 or BRCA2 mutation associated breast cancer. Cohorts receive escalating doses of ABT-888 orally BID days 1–14, CP 75 mg/m2 intravenously (IV) day 1 and V 25 mg/m2 IV days 1,8 every 21 days, in a 3+3 design. Results: As of 6/14/11, 18 eligible female pts have been enrolled. The median age at registration was 50 years (range 34–78 years). Sixteen pts received at least one prior metastatic regimen (range 0–8). Three pts had previously treated brain metastases. BRCA mutation status was as follows: BRCA1+ (3 pts); BRCA2+ (2 pts); confirmed mutation negative (8 pts); unknown (5 pts). Four pts received the 20 mg BID veliparib dose (one patient in the cohort died of progressive disease early in cycle 1 and was replaced), 3 received 30 mg BID, 6 received 40 mg BID, and 5 have been enrolled at dose level 4 (60 mg BID). Dose limiting toxicities occurred in one patient at the 40 mg BID dose (grade 4 thrombocytopenia), and one patient at the 60 mg BID dose (grade 3 neutropenic fever). Adverse events are typical for a platinum-based chemotherapy regimen and include nausea, fatigue, thrombocytopenia, and neutropenia. MTD has not been reached. Of 11 pts evaluable for radiographic response to date, 6 (55%) had a PR (3 of whom have a BRCA mutation) and 5 (45%) had stable disease. Correlative studies will use immunohistochemistry and gene expression array to evaluate the profile of TN breast cancer and predictors of response to treatment. Conclusion: Veliparib in combination with CP and V has been generally well tolerated to date. Objective anti-tumor activity was seen in BRCA mutation carriers and in pts with sporadic TN breast cancer. PK, PD, and biomarker analysis is underway. Enrollment continues in the dose escalation cohorts. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-04.

BRCA mutation testing in determining breast cancer therapy.

BRCA mutation-associated breast cancer differs from sporadic breast cancer with regard to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available at the time of breast cancer diagnosis, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA mutation carriers with breast cancer. This article reviews surgical options for management of affected BRCA mutation carriers with emphasis on the risks of ipsilateral recurrence and contralateral breast cancer. The roles of breast-conserving surgery, prophylactic mastectomy, and oophorectomy are reviewed. In addition, the sensitivity of BRCA mutation-associated breast cancer to endocrine therapy, platinum chemotherapy, and poly (ADP-ribose) polymerase inhibitors is reviewed.

C-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

BRCA1 mutation-associated breast cancer originates in oestrogen receptor-alpha-negative (ER(-)) progenitors in the mammary luminal epithelium. These cells also express high levels of the Kit gene and a recent study demonstrated a correlation between Brca1 loss and Kit over-expression in the mammary epithelium. However, the functional significance of c-Kit expression in the mammary gland is unknown. To address this, c-Kit(-) and c-Kit(+) mammary epithelial subsets were isolated by flow cytometry, characterised for expression of lineage-specific cell markers and functionally analysed by in vitro colony forming and in vivo transplantation assays. The results confirm that the majority of luminal ER(-) progenitors are c-Kit(+), but also that most stem cells and the differentiated cell populations are c-Kit(-). A subset of c-Kit(+) cells with high proliferative potential was found in the luminal ER(+) population, however, suggesting the existence of a distinct luminal ER(+) progenitor cell type. Analysis of mouse Brca1 mammary tumours demonstrated that they expressed Kit and its downstream effector Lyn at levels comparable to the most strongly c-Kit(+) luminal ER(-) progenitors. Consistent with c-Kit being a progenitor cell marker, in vitro three-dimensional differentiation of c-Kit(+) cells resulted in a loss of c-Kit expression, whereas c-Kit over-expression prevented normal differentiation in vivo. Furthermore, c-Kit was a functional marker of proliferative potential, as c-Kit inhibition by short hairpin knockdown prevented normal epithelial growth and caused cells to undergo apoptosis. Therefore, c-Kit defines distinct progenitor populations in the mammary epithelium and is critical for mammary progenitor survival and proliferation. Importantly, c-Kit is only the second mammary epithelial stem/progenitor marker to be shown to have a functional role in the mammary epithelium and the first marker to be shown to be required for progenitor cell function. The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer.

Risk of breast cancer (BC) after BRCA-mutation associated ovarian cancer (BRCA-OC): Memorial Sloan-Kettering Cancer Center (MSKCC) experience.

1518 Background: Women (W) with BRCA mutation-associated BC are at significant risk for metachronous OC, ranging from 0.8-1.5% per year. The risk of BC after a diagnosis (Dx) of BRCA-OC is unknown....

Abstract 1206: HER2/neu positive receptor status is associated with a low DNA repair capacity in women with breast cancer

Abstract Hormone receptor status are now routinely used for therapy selection in breast cancer (BC). Estrogen receptor status is routinely use for the selection of tamoxifen adjuvant therapy after surgery. Substantial evidence now indicates that patients with BC tumors that have overexpression of the HER2/neu receptor have generally a poor prognosis. Approximately 15-20 percent of BC patients have an amplification of the HER2/neu gene. Overexpression of HER2/neu is associated with increased BC recurrence and worse prognosis. Because of its prognostic role as well as its ability to predict response to trastuzumab (Herceptin), breast tumors are routinely checked for overexpression of HER2/neu. Strategies targeting DNA repair defects for the treatment of patients with triple-negative and BRCA mutation-associated BC have received much attention recently, however the relationship between HER2/neu receptor status and the phenotypic expression of DNA repair capacity (DRC) measured in lymphocytes has never been previously examined. DRC is an important risk factor for several types of cancer including BC. In this study, we examined the association between BC and DRC and the status of estrogen, progesterone and HER2/neu receptors. Our main objective was to determine if levels of DRC measured in lymphocytes using a host cell reactivation assay with a luciferase reporter gene are associated with receptor status. The estrogen, progesterone and HER2/neu receptor status, DRC levels, and other selected covariates were compared among 125 Hispanic women with histopathologically confirmed BC. After variable transformation, the mean DRC was compared between positive and negative HER2/neu BC patients using the t-test and the Wilcoxon's test to assess the statistical significance of the mean DRC difference. Crude and multiple logistic regression adjusted odds ratios (OR) were used as measures of association when compared HER2/neu (+) with (−) BC patients. The two-sided Wald test was used to assess the adjusted OR statistical significance. BC women with a HER2/neu (+) (n=14) had 4.1 times more odds of having a low DRC (&amp;lt; 1.78) compared with those that were HER2/neu (−) (n=65): (OR = 4.3 (95% CI 1.1, 16.6) p = 0.047. The average DRC in controls without BC was 6.10% (n=560). Women with BC that were HER2/neu (+) had an average DRC of 1.6% while BC patients that were HER2/neu (−) had 2.4%, this difference was significant (p=0.008). No significant differences were evident in regards to the association between DRC and the status of estrogen and progesterone receptors (double negatives) nor with triple negative receptor status (estrogen, progesterone and HER2/neu).These results indicate that low DRC could, at least partially explain, why HER2/neu (+) tumors are more aggressive. Supported by the NCI Diversity Training Branch of the Center to Reduce Cancer Health Disparities through the MBRS SCORE Program (Grant SO6 GM008239-23). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1206. doi:10.1158/1538-7445.AM2011-1206

The Cell of Origin of BRCA1 Mutation-associated Breast Cancer: A Cautionary Tale of Gene Expression Profiling

Breast tumours are highly heterogeneous with several distinct sub-types recognised according to their histological and molecular features. The biological basis for this heterogeneity is largely unknown, although there are some distinct phenotype-genotype correlations. These include BRCA1 mutation-associated breast cancers, which are typically high grade invasive ductal carcinomas of no special type (IDC-NSTs) with pushing margins that do not express estrogen receptor (ER), progesterone receptor (PR) or the HER2 receptor tyrosine kinase ('triple negative'). Gene expression analysis of these tumours has grouped them with so called 'basal-like' breast cancers and this, together with evidence that knock-down of BRCA1 in vitro blocked luminal differentiation, led to speculation that these tumours arose from the normal basal stem cells within the mammary gland. Recently, however, human breast tissue from BRCA1 mutation carriers was shown to contain an expanded population of luminal progenitor cells which have increased in vitro clonogenic ability. In the mouse, targeted deletion of Brca1 in luminal ER negative progenitors resulted in the formation of mammary tumours which phenocopied human BRCA1 breast tumour pathology, while the deletion of Brca1 in basal stem cells resulted in the formation of tumours which neither resembled human BRCA1 tumours or sporadic basal-like breast tumours. Importantly, however, both sets of mouse tumours were classified as 'basal-like' by methods used for human tumour classification based on gene expression profiles. This demonstrates that, as it stands, expression profiling is poor at distinguishing tumour histological subtypes and is also a poor guide to the cell of tumour origin. These human and rodent studies support an origin of BRCA1-mutation associated breast cancer (and indeed of the majority of sporadic basal-like breast cancers) in a luminal ER negative mammary epithelial progenitor. This is a key finding, as identification of the cells of origin in breast cancer subtypes makes possible the identification of key processes associated with initiation, progression and maintenance of each tumour subtype, the development of novel targeted therapies and, potentially, of new preventative approaches in high risk groups.

BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells

Breast cancers in BRCA1 mutation carriers frequently have a distinctive basal-like phenotype. It has been suggested that this results from an origin in basal breast epithelial stem cells. Here, we demonstrate that deleting Brca1 in mouse mammary epithelial luminal progenitors produces tumors that phenocopy human BRCA1 breast cancers. They also resemble the majority of sporadic basal-like breast tumors. However, directing Brca1 deficiency to basal cells generates tumors that express molecular markers of basal breast cancers but do not histologically resemble either human BRCA1 or the majority of sporadic basal-like breast tumors. These findings support a derivation of the majority of human BRCA1-associated and sporadic basal-like tumors from luminal progenitors rather than from basal stem cells. They also demonstrate that when target cells for transformation have the potential for phenotypic plasticity, tumor phenotypes may not directly reflect histogenesis. This has important implications for cancer prevention strategies.