Baseline Screening MRI Uptake and Findings in Women with ≥ 20% Lifetime Risk of Breast Cancer.

BACKGROUND: The American Cancer Society recommends screening magnetic resonance imaging (MRI) for patients with a ≥ 20% lifetime breast cancer risk. This study assesses the outcomes of baseline MRI screens in women from a high-risk breast clinic (HRBC). METHODS: We retrospectively reviewed patients from our institution's HRBC, excluding those with prior breast cancer and predisposing genetic mutations. Screening MRI was recommended for a lifetime risk of ≥ 20% using the Tyrer-Cuzick model. We determined baseline MRI results, biopsy rates, and frequency of MRI-detected high-risk lesions (HRLs) and breast cancers. RESULTS: Overall, 319 women attended our HRBC; median age was 48 years and 4.7% had prior atypia/lobular carcinoma in situ. Screening MRI was recommended for 282 patients, of whom 196 (69.5%) completed a baseline screen. A Breast Imaging-Reporting and Data System (BIRADS) 3 or 4 finding occurred in 19.6% of patients; 23 (12.3%) required 6-month follow-up MRI, 16 (8.6%) underwent core biopsy, and 4 (2.1%) underwent excisional biopsy after initial core. An additional 7 (3.7%) patients had a non-breast incidental finding. An HRL was identified in 2 (1.1%) patients (atypical ductal and lobular hyperplasia, respectively), and 2 (1.1%) were diagnosed with T1N0 breast cancers. CONCLUSIONS: In the setting of an HRBC, 70% of women with a ≥ 20% lifetime risk of breast cancer pursued screening MRI when recommended. On baseline screen, the rate of MRI-detected breast cancer was low (1%); however, malignancies were mammographically occult and identified at an early stage. Despite a low cancer rate, nearly one in four women required additional diagnostic investigation. Prescreening counselling should include a discussion of this possibility, and longer-term follow-up of screening MRI is needed in this high-risk population.

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. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. RESULTS: Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. CONCLUSION: Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted.

Delta-6-desaturase activity and arachidonic acid synthesis are increased in human breast cancer tissue.

Omega-6 (n-6) arachidonic acid (AA) and its pro-inflammatory metabolites, including prostaglandin E2 (PGE(2)), are known to promote tumorigenesis. Delta-6 desaturase (D6D) is the rate-limiting enzyme for converting n-6 linoleic acid (LA) to AA. Our objective was to determine if AA synthesis, specifically D6D activity, and PGE(2) levels are increased in cancerous breast tissue, and whether these variables differ between estrogen receptor positive (ER+) and negative (ER-) breast cancers. Gas chromatography was performed on surgical breast tissue samples collected from 69 women with breast cancer. Fifty-four had ER+ breast cancer, and 15 had ER- breast cancer. Liquid chromatography-mass spectrometry was used to determine PGE(2) levels. Lipid analysis revealed higher levels of LA metabolites (C18:3 n-6, C20:3 n-6, and AA) in cancerous tissue than in adjacent noncancerous tissue (P < 0.01). The ratio of LA metabolites to LA, a measure of D6D activity, was increased in cancerous tissue, suggesting greater conversion of LA to AA (P < 0.001), and was higher in ER- than in ER+ patients, indicating genotype-related trends. Similarly, PGE(2) levels were increased in cancerous tissue, particularly in ER- patients. The results showed that the endogenous AA synthetic pathway, D6D activity, and PGE(2) levels are increased in breast tumors, particularly those of the ER- genotype. These findings suggest that the AA synthetic pathway and the D6D enzyme in particular may be involved in the pathogenesis of breast cancer. The development of drugs and nutritional interventions to alter this pathway may provide new strategies for breast cancer prevention and treatment.

Phase II prospective study of paclitaxel and carboplatin in older patients with newly diagnosed Müllerian tumors.

OBJECTIVES: The primary objective was to determine the completion rate of 6 cycles of paclitaxel and carboplatin chemotherapy with no dose reductions in patients > or =70 years of age. METHODS: Phase II study of intravenous (IV) carboplatin Area Under the Curve (AUC) of 5 and paclitaxel 175 mg/m(2) given to patients > or =70 years of age, had any stage Müllerian cancer, and an ECOG performance status (PS) of 0-2. RESULTS: Twelve patients were enrolled (median age of 82 years, range 75 to 86 years). Six of 12 completed 6 cycles of chemotherapy with no dose reductions. Three patients died on study precipitating study closure; one with refractory cancer following cycle 1, one of aspiration pneumonia after cycle 1, and one with sudden death on day 5 of cycle 6. Patients undergoing upfront debulking surgery tolerated chemotherapy better compared to patients receiving neoadjuvant chemotherapy. Grade 3 or higher hematologic toxicities included 2 patients with febile neutropenia (17%). > or =Grade 3 non-hematologic toxicities included fatigue (8%), nausea (8%), constipation (8%), obstipation (8%), vomiting (8%), and hypoxia (8%). CONCLUSIONS: In this prospective trial of standard carboplatin and paclitaxel chemotherapy in a heterogeneous population of elderly patients, chemotherapy was well tolerated by patients who underwent upfront debulking surgery, had a PS of 0-1, and had few comorbidities. Patients not undergoing upfront debulking surgery because of either advanced cancer or poor surgical risk had excess morbidity/mortality. Prospective studies to identify risk factors for toxicity prediction are needed.