A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer.

Purpose: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab.

Methods: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B).

TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer.

Purpose: The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates.

Patients And Methods: Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks.

Multifocal and multicentric breast cancer is associated with increased local recurrence regardless of surgery type.

Multifocal and multicentric breast cancers have been correlated with poor prognostic factors and worse outcomes versus unifocal disease. We evaluated the impact of multifocal and multicentric disease versus case controls with unifocal disease, matching for age, grade, T-, and N-stage. A total of 110 patients with multifocal (n = 93) or multicentric (n = 17) disease and 263 matched case controls were identified with a median follow-up of 53 months and 64 months, respectively.

Young adult daughters of BRCA1/2 positive mothers: what do they know about hereditary cancer and how much do they worry?

Objective: The objectives of this study are to determine (i) what daughters, ages 18-24 years, of BRCA1/2 mutation carriers understand about their 50% chance of carrying a BRCA1/2 mutation and about risk reduction or management options for mutation carriers, (ii) the extent and nature of daughters' cancer-related distress, and (iii) the effects of knowing mother's mutation status on daughters' future plans.

Methods: A total of 40 daughters, currently aged 18-24 years, of mothers who tested positive for a mutation in BRCA1/2 were invited by mail to participate (with contact information supplied by their mothers). Daughters participated in a qualitative telephone interview about the impact of learning their mother's mutation status on their understanding of their own cancer risks and their cancer-related distress, and their knowledge of screening strategies, risk-reducing surgery, current health status, and future plans.

Cost-effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers.

Background: Current clinical guidelines recommend earlier, more intensive breast cancer screening with both magnetic resonance imaging (MRI) and mammography for women with breast cancer susceptibility gene (BRCA) mutations. Unspecified details of screening schedules are a challenge for implementing guidelines.

Methods: A Markov Monte Carlo computer model was used to simulate screening in asymptomatic women who were BRCA1 and BRCA2 mutation carriers.

Metastatic mucinous ovarian cancer and treatment decisions based on histology and molecular markers rather than the primary location.

Approximately 22,000 cases of ovarian cancer occur each year in the United States, and likely fewer than 2000 cases of mucinous ovarian cancers. Although 90% of patients with mucinous ovarian cancer present with stage I disease and have curative surgeries, advanced-stage disease is known to have a poor response to standard platinum- and taxane-based chemotherapy. Despite limited enthusiasm, standard chemotherapy is still recommended for most patients with advanced-stage mucinous malignancies of the ovary.

Faciocutaneous cancer syndromes: spot the diagnosis.

This commentary highlights the potential for early diagnosis of certain cancers diagnoses for individuals with hereditary faciocutaneous disorders.

Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.

Unlabelled: DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity.

Which individuals undergoing BRACAnalysis need BART testing?

Deleterious mutations in BRCA1 and BRCA2 include those identified by sequencing technology as well as large genomic rearrangements (LGR). The main testing laboratory in the United States, Myriad Genetics Laboratory (MGL), has defined criteria for inclusion of LGR testing (i.e.

Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis.

Background: Although breast cancer screening with mammography and magnetic resonance imaging (MRI) is recommended for breast cancer-susceptibility gene (BRCA) mutation carriers, there is no current consensus on the optimal screening regimen.

Methods: The authors used a computer simulation model to compare 6 annual screening strategies (film mammography [FM], digital mammography [DM], FM and magnetic resonance imaging [MRI] or DM and MRI contemporaneously, and alternating FM/MRI or DM/MRI at 6-month intervals) beginning at ages 25 years, 30 years, 35 years, and 40 years, and 2 strategies of annual MRI with delayed alternating DM/FM versus clinical surveillance alone. Strategies were evaluated without and with mammography-induced breast cancer risk using 2 models of excess relative risk.

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.

Cost-effectiveness of breast MR imaging and screen-film mammography for screening BRCA1 gene mutation carriers.

Purpose: To evaluate the clinical effectiveness and cost-effectiveness of screening strategies in which MR imaging and screen-film mammography were used, alone and in combination, in women with BRCA1 mutations.

Materials And Methods: Because this study did not involve primary data collection from individual patients, institutional review board approval was not needed. By using a simulation model, we compared three annual screening strategies for a cohort of 25-year-old BRCA1 mutation carriers, as follows: (a) screen-film mammography, (b) MR imaging, and (c) combined MR imaging and screen-film mammography (combined screening).

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.

Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer.

PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response.

VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy.

Background: Anti-vascular endothelial growth factor therapy (VEGF) is an important new treatment modality in oncology. We sought to determine the efficacy and safety of the humanized monoclonal anti-VEGF antibody, bevacizumab, and vinorelbine as treatment for refractory breast cancer and to explore the role of plasma VEGF as a predictor of treatment outcome.

Experimental Design: Eligible patients had received one or two prior chemotherapy regimens for metastatic breast cancer or recurred within 12 months of adjuvant therapy and had measurable disease and adequate end-organ function.

Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort.

Purpose: Most node-negative breast cancer patients are older and postmenopausal and are increasingly being offered adjuvant chemotherapy despite their low overall risk of distant relapse. A molecular diagnostic test with high negative predictive value (NPV) for distant metastasis in this subgroup would spare many older breast cancer patients adjuvant treatment.

Experimental Design: We determined the NPV and positive predictive value of the MammaPrint assay in breast cancer patients who were consecutively diagnosed and treated at the Massachusetts General Hospital between 1985 and 1997.

Professional challenges in cancer genetic testing: who is the patient?

In the genetic counseling setting, the health care provider can be challenged by opposing duties to members of the same family: protecting the privacy of the patient identified with a gene mutation and the ethical obligation to warn at-risk relatives. In a situation of nondisclosure between members of a family with a known disease-predisposing mutation, this type of dilemma can present in acute form for the provider who cares for different members of the family. This can hinder effective medical decision making.

Breast cancer screening in BRCA1 mutation carriers: effectiveness of MR imaging--Markov Monte Carlo decision analysis.

Purpose: To project intermediate and long-term clinical outcomes of magnetic resonance (MR) imaging screening for breast cancer in women with BRCA1 gene mutations.

Materials And Methods: A microsimulation model was developed to compare three annual screening strategies versus clinical surveillance: (a) mammography, (b) MR imaging, and (c) combined MR imaging and mammography. Input parameters were obtained from the published medical literature, existing databases, and expert opinion.

The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer.

The insulin-like growth factor signaling pathway is important in many human cancers based on data from experimental models as well as epidemiological studies. Important therapies targeted at this pathway have been or are being developed, including monoclonal antibodies to the insulin-like growth factor-I receptor and small molecule inhibitors of the tyrosine kinase function of this receptor. These investigational therapies are now being studied in clinical trials.

Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer.

Purpose: To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

Experimental Design: Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response.

Uptake of BRCA1 rearrangement panel testing: in individuals previously tested for BRCA1/2 mutations.

Purpose: Individuals undergoing genetic testing for BRCA1/2 mutations are routinely counseled about the sensitivity and specificity of testing. In August 2002, testing for 5 large genomic rearrangements in the BRCA1 gene that would not have been detected with full gene sequence analysis became commercially available. We present our data on uptake of the BRCA1 rearrangement panel testing in our clinical cancer genetics program.

Adjuvant hormonal therapy in peri- and postmenopausal breast cancer.

Tamoxifen has been the mainstay of endocrine treatment for early-stage breast cancer in both premenopausal and postmenopausal women for many years. Since 2001, the results of several large, randomized, clinical trials have provided evidence that aromatase inhibitor (AI) therapy, either upfront or in sequence after tamoxifen, improves disease-free survival and, in certain patients, overall survival for postmenopausal patients with hormone receptor-positive breast cancer. Thus far, with relatively short-term follow-up, AIs have been generally safe and well tolerated among the population of patients treated in these adjuvant trials.