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). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22-13.6) on Arm A and 1.82 months (1.54-6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2-NA) on Arm A and 16.2 months (15.7-NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. CONCLUSION: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. CLINICALTRIALS: gov Identifier: NCT00083031. Date of Registration: May 17, 2004.

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting.

OBJECTIVE: To examine the real-world incidence and management of select adverse events (AEs) among female patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), receiving a cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitor (palbociclib, abemaciclib, or ribociclib). METHODS: This retrospective study analyzed data from the US Oncology Network iKnowMed electronic health record database for 396 patients with an initial MBC diagnosis on/after 1 January 2014 and receipt of first CDK4 and 6 regimen between 1 January 2017 and 31 December 2018. In this descriptive study, the proportion of patients who experienced select AEs and associated dose modifications or discontinuations were reported. The occurrence of select healthcare resource utilization categories was also reported. RESULTS: Median follow-up time was 451, 262, and 355 days for patients in the palbociclib, abemaciclib, and ribociclib cohorts, respectively. The most common AEs were neutropenia (palbociclib, 44.8%; abemaciclib, 10.6%; ribociclib, 36.3%), diarrhea (palbociclib, 8.0%; abemaciclib, 43.0%; ribociclib, 8.8%), and fatigue (palbociclib, 12.9%; abemaciclib, 17.6%; ribociclib, 16.5%). AEs resulted in a treatment hold among 91 (23.0%), a dose reduction among 86 (21.7%), and permanent discontinuation among 48 (12.1%) patients overall. CONCLUSIONS: This real-world study provides insight into the occurrence of AEs which varied by CDK4 and 6 inhibitor. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible these differences reflect proactive management of AEs on the part of clinicians to help patients remain on therapy.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6 inhibitors) have changed the landscape for the treatment of metastatic breast cancer (MBC) among patients who are hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−). An understanding of the real-world management of adverse events (AEs) will help optimize treatment strategies. Here, data from the US Oncology Network electronic health record database for 396 HR+, HER2−, MBC patients receiving a CDK4 and 6 inhibitor were examined to describe the proportion of patients who experienced select AEs and the associated outcomes of these AEs. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible that these differences reflect a proactive management of AEs on the part of clinicians to help patients remain on therapy.

Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.

PURPOSE: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). EXPERIMENTAL DESIGN: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy. RESULTS: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. CONCLUSIONS: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.

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.

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. The actuarial local control rates for the multifocal/multicentric and unifocal group were 88% and 97%, respectively at both 5 and 10 years (p < 0.001). On multivariate analysis, multifocal/multicentric disease remained associated with higher local recurrence after controlling for other covariates including surgery type. The disease-free survival rates in the multifocal/multicentric group at 5 and 10 years were 75% and 71%, respectively, versus 87% and 78% at 10 years (p = 0.01). On multivariate analysis, multifocal/multicentric disease was no longer associated with worse disease-free survival. There was no difference in the cohorts in terms of regional control, overall survival, or cancer specific survival. Our findings suggest that multifocal/multicentric disease may be associated with worse outcomes versus unifocal disease regardless of type of surgery. This suggests a more biologically aggressive cancer and may be an important consideration when managing these patients. Further studies are needed to better understand the impact of multifocal/multicentric breast cancers on outcomes.

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. Participants also completed study-specific demographic and family history questionnaires, the Brief Symptom Inventory-18, Impact of Event Scale (with hereditary predisposition to breast/ovarian cancer as the event), and the Breast Cancer Genetic Counseling Knowledge Questionnaire. RESULTS: Daughters' genetic knowledge is suboptimal; gaps and misconceptions were common. Over 1/3 of the daughters reported high cancer-related distress, despite normal levels of general distress. Disclosed genetic information raised future concerns, especially regarding childbearing. CONCLUSION: Targeted professional attention to this high-risk cohort of young women is critical to inform the next generation of daughters of BRCA1/2 mutation carriers and encourage recommended screening by age 25 years. Improved uptake of screening and risk reduction options could improve survival, and psychoeducation could reduce cancer-related distress.

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. Three dual-modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6-month intervals beginning at age 25 years (Alt25), 2) annual MRI beginning at age 25 years with alternating DM added at age 30 years (MRI25/Alt30), and 3) DM and MRI alternating at 6-month intervals beginning at age 30 years (Alt30). Primary outcomes were quality-adjusted life years (QALYs), lifetime costs (in 2010 US dollars), and incremental cost-effectiveness (dollars per QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs). RESULTS: All 3 dual-modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained (BRCA1, $74,200 per QALY; BRCA2, $215,700 per QALY). False-positive test results increased substantially with dual-modality screening and occurred more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up-front screening and diagnosis costs. The results were influenced most by estimates of breast cancer risk and MRI costs. CONCLUSIONS: Alternating MRI and DM screening at 6-month intervals beginning at age 30 years was identified as a clinically effective approach to applying current guidelines, and was more cost-effective in BRCA1 gene mutation carriers compared with BRCA2 gene mutation carriers.

Circulating tumor cells as predictors of response and failure in breast cancer patients treated with preoperative chemotherapy.

AIM: To explore the significance of circulating tumor cells (CTCs) detection in the course of preoperative chemotherapy (PC) and their effect on the outcomes.
 METHODS: Fifty-five patients with stage II/III invasive breast cancer were enrolled into a preoperative clinical trial. Patients were given PC with sequential single-agent doxorubicin and paclitaxel vs paclitaxel followed by doxorubicin. Blood samples (8 mL) were collected from patients before PC, after each phase, and at 6 months intervals during follow-up. Peripheral blood mononuclear cells were isolated and enriched for epithelial cells. Quantitative RT-PCR was used to determine the presence of cytokeratin 19 (CK19) mRNA. Samples were considered positive when the PCR curve crossed the standard threshold curve.
 RESULTS: After the first phase of chemotherapy, there was a 59% overall reduction in the median tumor volume. The percentage of volume reduction did not differ between patients who presented with detectable CTCs at baseline and those who did not (p=0.89). After the second phase of chemotherapy, there was a further decrease in the median tumor volume to 93% from baseline. There was no correlation between the lack of response and the presence of CTCs either after the first (p=0.36) or second (p=0.5391) phases of PC. The presence of CTCs was a predictor of local or distant relapse (p=0.0411). The detection of CTCs did not affect overall survival (p=0.2569).
 CONCLUSION: CTCs can be used as predictors of relapse after definitive treatment of locally advanced breast cancer; however, CTCs detection in peripheral blood during the course of PC does not implicate a particular pattern of response to treatment.

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. This report presents an unusual case of a woman with HER2-positive metastatic mucinous carcinoma of the ovary treated with chemotherapy regimens typically used for colorectal malignancies, followed by epidermal growth factor receptor-targeted therapies.

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. The number of subchromosomal regions with allelic imbalance extending to the telomere (N(tAI)) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of N(tAI) forecast a better initial response. We found an inverse relationship between BRCA1 expression and N(tAI) in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair. SIGNIFICANCE: Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair.

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. Input parameters were obtained from the medical literature, publicly available databases, and calibration. RESULTS: Without radiation risk effects, alternating DM/MRI starting at age 25 years provided the highest life expectancy (BRCA1, 72.52 years, BRCA2, 77.63 years). When radiation risk was included, a small proportion of diagnosed cancers was attributable to radiation exposure (BRCA1, <2%; BRCA2, <4%). With radiation risk, alternating DM/MRI at age 25 years or annual MRI at age 25 years/delayed alternating DM at age 30 years was the most effective, depending on the radiation risk model used. Alternating DM/MRI starting at age 25 years also produced the highest number of false-positive screens per woman (BRCA1, 4.5 BRCA2, 8.1). CONCLUSIONS: Annual MRI at age 25 years/delayed alternating DM at age 30 years is probably the most effective screening strategy in BRCA mutation carriers. Screening benefits, associated risks, and personal acceptance of false-positive results should be considered in choosing the optimal screening strategy for individual women.

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., BRACAnalysis Rearrangement Test, or BART™) when BRCA1 and BRCA2 testing is ordered. We were interested in determining how many of our patients with LGR mutations in BRCA1 and BRCA2 fulfilled these MGL criteria. A retrospective chart review was performed on all individuals who underwent genetic testing at our institution since August 2006. Individuals who underwent LGR testing were classified as either having or not having a LGR in BRCA1 or BRCA2. Each individual's history was classified as meeting MGL defined LGR criteria, meeting criteria using third-degree relatives, or not meeting criteria. A total of 257 BART tests were ordered at our institution from August 2006 to August 2009. Five individuals (1.9%) had an LGR mutation. Two LGR were identified in patients who met MGL defined LGR criteria. One LGR was identified in a patient that met MGL defined LGR criteria only when using third-degree relatives. Two LGR were identified in individuals who did not meet MGL defined criteria. LGR are present in individuals who do not have a high pretest probability of carrying a mutation in BRCA1 or BRCA2. These data suggest that when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR testing so that the results are the most comprehensive and reliable.

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. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers. METHODS: Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers. RESULTS: Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞). CONCLUSIONS: We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.

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). The model was used to estimate quality-adjusted life-years (QALYs) and lifetime costs. Incremental cost-effectiveness ratios were calculated. Input parameters were obtained from the medical literature, existing databases, and calibration. Costs (2007 U.S. dollars) and quality-of-life adjustments were derived from Medicare reimbursement rates and the medical literature. Sensitivity analysis was performed to evaluate the effect of uncertainty in parameter estimates on model results. RESULTS: In the base-case analysis, annual combined screening was most effective (44.62 QALYs), and had the highest cost ($110973), followed by annual MR imaging alone (44.50 QALYs, $108641), and annual mammography alone (44.46 QALYs, $100336). Adding annual MR imaging to annual mammographic screening cost $69125 for each additional QALY gained. Sensitivity analysis indicated that, when the screening MR imaging cost increased to $960 (base case, $577), or breast cancer risk by age 70 years decreased below 58% (base case, 65%), or the sensitivity of combined screening decreased below 76% (base case, 94%), the cost of adding MR imaging to mammography exceeded $100000 per QALY. CONCLUSION: Annual combined screening provides the greatest life expectancy and is likely cost-effective when the value placed on gaining an additional QALY is in the range of $50000-$100000. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.09091086/-/DC1.

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. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers. RESULTS: BRCA1 carriers aged > or = 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04). CONCLUSIONS: BRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.

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. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.

Circulating tumor cells in HER-2 positive metastatic breast cancer patients treated with trastuzumab and chemotherapy.

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2 positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment 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. Patients received bevacizumab 10 mg/kg every 2 weeks, and vinorelbine each week, until tumor progression or prohibitive toxicity. Plasma VEGF was measured at baseline. RESULTS: Among 56 women treated on protocol, bevacizumab and vinorelbine yielded a 34% response rate (95% confidence interval, 22-48%) and median time to progression of 5.5 months. Activity was observed regardless of tumor hormone receptor status or type or extent of prior chemotherapy. Side effects included uncomplicated neutropenia, hypertension, nasal congestion/epistaxis, and neuropathy, consistent with well-described side effects of the respective agents. Three patients had impaired wound healing following surgical procedures. There were only rare instances of thrombosis or clinically significant proteinuria. Lower levels of baseline VEGF were associated with longer time to progression. CONCLUSIONS: Bevacizumab and vinorelbine are well tolerated and effective as treatment for refractory breast cancer. Plasma VEGF warrants further evaluation as a prognostic marker for treatment outcome in advanced breast cancer patients receiving anti-VEGF therapy.