Immunohistochemical findings and clinicopathological features of breast cancers with pathogenic germline mutations in Non-BRCA genes.

Deleterious germline mutations in multiple genes confer an increased breast cancer (BC) risk. Immunohistochemical (IHC) expression of protein products of mutated high-risk genes has not been investigated in BC. We hypothesized that pathogenic mutations may lead to an abnormal IHC expression pattern in the tumor cells.

Neoadjuvant weekly paclitaxel and carboplatin with trastuzumab and pertuzumab in HER2-positive breast cancer: a Brown University Oncology Research Group (BrUOG) study.

Purpose: In HER2-positive breast cancer (HER2+ BC), neoadjuvant chemotherapy (NACT) with dual HER2-targeted therapy achieves high pathologic complete response (pCR) rates. Anthracycline-free NACT regimens avoid toxicities associated with anthracyclines, but every 3-week TCHP also has substantial side effects. We hypothesized that a weekly regimen might have equivalent efficacy with less toxicity; we also investigated whether poorly responding patients would benefit from switching to AC.

TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline Carriers With HER2-Negative Breast Cancer (the INFORM trial).

Purpose: Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline mutation carriers ( carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

Choosing high-risk screening surgery and the effect of treatment modality on anxiety and breast-specific sensuality in BRCA mutation carriers.

Background: We have previously shown that breast cancer surgery affects breast specific sensuality, and that women who undergo mastectomy may have worse sexual function outcomes than those who undergo lumpectomy. It is less clear if patients who undergo prophylactic mastectomy are equally as affected as those with a cancer diagnosis. We sought to compare sexual function outcomes and their relationship to depression and anxiety between BRCA mutation carriers (mBRCA) with and without cancer in order to guide surgical counseling and improve survivorship outcomes.

Creating a Just Culture: The Ottawa Hospital's experience.

We describe The Ottawa Hospital's (TOH) journey to create a Just Culture. We will describe the concept of a Just Culture, why TOH initiated this transformation, how TOH went about creating the Just Culture, and some of its early impacts. Following two events that called into question our hospital's safety culture, the hospital leadership adopted a deliberate and methodical organization-wide approach to change.

Advances in Medical Management of Early Stage and Advanced Breast Cancer: 2015.

Standard management of early stage and advanced breast cancer has been improved over the past few years by knowledge gained about the biology of the disease, results from a number of eagerly anticipated clinical trials and the development of novel agents that offer our patients options for improved outcomes or reduced toxicity or both. This review highlights recent major developments affecting the systemic therapy of breast cancer, broken down by clinically relevant patient subgroups and disease stage, and briefly discusses some of the ongoing controversies in the treatment of breast cancer and promising therapies on the horizon.

Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetic professionals.

Objective: Genetic predisposition is responsible for 5-10% of breast cancer, 10% of ovarian cancer and 2-5% of uterine cancer. The study objective was to compare genetic counseling and testing referral rates among women with breast cancer that met NCCN referral guidelines to the referral rates among women with gynecologic cancers and determine predictors of referral.

Methods: Utilizing an institutional tumor registry database, patients from an academic women's oncology program were identified who met a subset of NCCN guidelines for genetic referral between 2004 and 2010.

Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial.

Purpose: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3-activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS).

Experimental Design: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 10(9) armed ATC (aATC) per infusion.

Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers.

Introduction: The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency.

Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features.

Introduction: Most breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors.

Methods: Clinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared.

Clinical characteristics and choices regarding risk-reducing surgery in BRCA mutation carriers.

Background/aims: BRCA mutation carriers have a high lifetime risk of developing breast and ovarian malignancies. As genetic testing becomes widely available, preventative measures are a choice. We evaluated the characteristics of BRCA mutation carriers who chose prophylactic surgery (PS) compared to those who opted for surveillance.

Addressing clinical trials: can the multidisciplinary Tumor Board improve participation? A study from an academic women's cancer program.

Objective: The Tumor Board (TB) allows for an interdisciplinary approach to cancer treatment designed to encourage evidence-based treatment. However, its role in facilitating clinical trial participation has not been reported. We aimed to determine whether a prospective TB is an effective strategy for trial recruitment and to identify steps within the TB process that facilitate discussion of trial eligibility and optimize accrual.

Management of hematological malignancies during pregnancy.

The management of hematological malignancies during pregnancy is a challenging endeavor, which not only requires technical skills and knowledge by the clinicians but also requires sound clinical judgment and compassion, keeping in mind the patient and family preferences and, ultimately, the wellbeing of the neonate. The incidence of hematological malignancies during pregnancy is rare, ranging from 1 in 1,000 to 1 in 10,000 deliveries, impeding the design and execution of large prospective studies. The purpose of this review is to evaluate the limited existing data and make useful suggestions in the management of acute and chronic leukemias, Hodgkin and non-Hodgkin lymphomas, plasma cell myeloma, and other hematological malignancies, such as myelodysplastic syndromes and hairy cell leukemia, during pregnancy.

Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study.

Purpose: To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel +/- weekly trastuzumab in resectable and locally advanced breast cancer.

Patients And Methods: Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m(2) weekly for 16 weeks, and weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) -positive status. The primary end point was the pathologic complete response (pCR) rate, defined as the absence of invasive disease in the breast and axillary nodes.

For women receiving chemotherapy for clinically apparent early ovarian cancer, is there a benefit to surgical staging?

Background: For women with early stage ovarian cancer (ESOC), comprehensive staging is the standard of care and studies suggest that these patients may not require further treatment. For women with incidentally diagnosed ovarian cancer there is a lack of consensus as to whether surgical staging be performed, particularly if chemotherapy is recommended.

Objective: We performed this retrospective study to determine the outcomes of women treated with chemotherapy for clinically apparent ESOC, stratified by whether staging was performed or not.

Does the platinum-free interval predict the incidence or severity of hypersensitivity reactions to carboplatin? The experience from Women and Infants' Hospital.

Objectives: Carboplatin (C) is a standard treatment for gynecologic cancers, but its use in recurrence is associated with an increased risk of hypersensitivity reactions (HSR) in those previously treated with C. However, there is no way to predict those at risk for a C-HSR. We sought to evaluate whether the platinum-free interval (PFI) was predictive of incidence and severity of HSRs.

Two for good measure: six versus eight cycles of carboplatin and paclitaxel as adjuvant treatment for epithelial ovarian cancer.

Introduction: Although the standard of care for advanced epithelial ovarian cancer (EOC) is six cycles (6C) of platinum-taxane (PT), there have been no studies on the optimal duration of treatment in the era of adjuvant taxanes. At our center, some women receive eight cycles (8C) of PT, based on physician judgment. We were interested in evaluating the outcomes of women treated with 8C of PT for EOC as compared to a cohort who received 6C.

Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program.

Purpose: With the use of steroid premedication, the incidence of severe hypersensitivity reactions (S-HSR) to paclitaxel is estimated to be 2%. For those who develop a S-HSR to paclitaxel, docetaxel has been employed as an alternative agent though the presence of cross-sensitivity has not been established. We sought to define the incidence of S-HSR to docetaxel following a paclitaxel S-HSR in an academic women's cancer program.

PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.

FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL.

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.

Background: Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.

Adjuvant therapy in breast cancer.

The new millennium ushers in an exciting time in the treatment of early stage breast cancer. Although worldwide incidence statistics have not changed significantly in the past decade, mortality rates have declined. This change seems to be related to public health initiatives that increase early detection and awareness and to an increase in the efficacy of adjuvant treatments, including advances in chemotherapy and the emergence of biologic treatments.

Risk factors for breast cancer.

Breast cancer is multifaceted, and multiple risk factors most likely contribute to each case of the disease. Through further elucidation of highly penetrant autosomal dominant mutations and, perhaps more importantly, weaker polygenic influences, rational therapies to treat or prevent malignancy may develop. Determining the nature and sequence of genetic changes in premalignant breast tissue may offer the greatest opportunity to alter the process of breast cancer development.