Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

Advancing Evidence Generation for Circulating Tumor DNA: Lessons Learned from A Multi-Assay Study of Baseline Circulating Tumor DNA Levels across Cancer Types and Stages.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

Comprehensive Review on the Clinical Impact of Next-Generation Sequencing Tests for the Management of Advanced Cancer.

PURPOSE: This review summarizes the published evidence on the clinical impact of using next-generation sequencing (NGS) tests to guide management of patients with cancer in the United States. METHODS: We performed a comprehensive literature review to identify recent English language publications that presented progression-free survival (PFS) and overall survival (OS) of patients with advanced cancer receiving NGS testing. RESULTS: Among 6,475 publications identified, 31 evaluated PFS and OS among subgroups of patients who received NGS-informed cancer management. PFS and OS were significantly longer among patients who were matched to targeted treatment in 11 and 16 publications across tumor types, respectively. CONCLUSION: Our review indicates that NGS-informed treatment can have an impact on survival across tumor types.

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

PURPOSE: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. PATIENTS AND METHODS: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. RESULTS: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen. CONCLUSIONS: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

False-positive screening events and worry influence decisions about surgery among high-risk women.

OBJECTIVE: Studies of cancer screening have found that false positive screening events (FPSE) can affect worry about cancer risk and screening program use, we sought to further explore this. METHOD: In a study of 1,100 women at high risk for ovarian cancer who participated in a previously published randomized controlled trial (RCT), we sought to explore whether worry might also influence the use of risk-reducing surgical procedures by women. Participants included 234 women with BRCA1/2 mutations and 866 women with high-risk pedigrees. We followed the women for up to 6 years. RESULTS: Worry predicted risk reducing prophylactic bilateral salpingo-oophorectomy (pBSO) for both mutation carriers (HR = 1.74; p = .02), and women with high-risk pedigree (HR = 3.41; p < .001). FPSE also predicted subsequent pBSO among women with a high-risk pedigree (HR 2.31; p < .01). While screening may reduce worry among those who never receive a positive result, FPSE increase worry at least temporarily. Worry about ovarian cancer risk predicted use of preventative pBSO among high-risk women including those with BRCA1/2 mutations enrolled in an ovarian cancer-screening program. FPSE also predicted risk-reducing ovarian surgery among high-risk women without a known mutation at the time of screening program enrollment. CONCLUSIONS: Physicians who offer screening should know that false positive results may increase use of pBSO, how this should effect clinical practice is unclear. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Metastatic breast cancer cells overexpress and secrete miR-218 to regulate type I collagen deposition by osteoblasts.

BACKGROUND: Bone is one of the most frequent metastatic sites of advanced breast cancer. Current therapeutic agents aim to inhibit osteoclast-mediated bone resorption but only have palliative effects. During normal bone remodeling, the balance between bone resorption and osteoblast-mediated bone formation is essential for bone homeostasis. One major function of osteoblast during bone formation is to secrete type I procollagen, which will then be processed before being crosslinked and deposited into the bone matrix. METHODS: Small RNA sequencing and quantitative real-time PCR were used to detect miRNA levels in patient blood samples and in the cell lysates as well as extracellular vesicles of parental and bone-tropic MDA-MB-231 breast cancer cells. The effects of cancer cell-derived extracellular vesicles isolated by ultracentrifugation and carrying varying levels of miR-218 were examined in osteoblasts by quantitative real-time PCR, Western blot analysis, and P1NP bone formation marker analysis. Cancer cells overexpressing miR-218 were examined by transcriptome profiling through RNA sequencing to identify intrinsic genes and pathways influenced by miR-218. RESULTS: We show that circulating miR-218 is associated with breast cancer bone metastasis. Cancer-secreted miR-218 directly downregulates type I collagen in osteoblasts, whereas intracellular miR-218 in breast cancer cells regulates the expression of inhibin ß subunits. Increased cancer secretion of inhibin ßA results in elevated Timp3 expression in osteoblasts and the subsequent repression of procollagen processing during osteoblast differentiation. CONCLUSIONS: Here we identify a twofold function of cancer-derived miR-218, whose levels in the blood are associated with breast cancer metastasis to the bone, in the regulation of type I collagen deposition by osteoblasts. The adaptation of the bone niche mediated by miR-218 might further tilt the balance towards osteolysis, thereby facilitating other mechanisms to promote bone metastasis.

Identifying post-menopausal women at elevated risk for epithelial ovarian cancer.

OBJECTIVE: We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma. METHODS: To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data. RESULTS: Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7years of enrollment (HR=4.6, p<0.001). CONCLUSION: CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.

Inflammatory Biomarkers, Comorbidity, and Neurocognition in Women With Newly Diagnosed Breast Cancer.

BACKGROUND: Neurocognitive dysfunction is reported in women with breast cancer even prior to receipt of adjuvant therapy; however, there is little understanding of underlying mechanisms. We tested the hypothesis that pretreatment neurocognitive dysfunction in newly diagnosed patients is related to immunological activation, as indexed by pro-inflammatory cytokines. METHODS: One hundred seventy-four postmenopausal patients with newly diagnosed breast cancer underwent a comprehensive neuropsychological evaluation (assessment of cognitive function, mood, and fatigue) and measurement of key cytokine levels prior to surgery. Age-matched control participants without cancer were evaluated concurrently. Multivariable regression analyses examined the contribution of circulating Interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and soluble TNF receptor type two (sTNF-RII) in predicting neurocognitive performance in patients after controlling for key factors thought to impact functioning. All tests of statistical significance were two-sided. RESULTS: Memory performance was statistically significantly reduced, in patients compared with controls (P = .02). Of the three cytokines measured, only IL-1ra was statistically significantly elevated in cancer patients when compared with control participants (mean ± SD, 375 ± 239 pg/mL vs 291 ± 169 pg/mL, P = .007). After controlling for age, education, race, mood, fatigue, body mass index, and comorbidity, cytokines independently explained 6.0% of the total variance in memory performance (P = .01) in cancer patients but not control participants, with higher sTNF-RII associated with worse functioning. Exploratory analyses found that comorbidity statistically significantly explained variance in processing speed and executive functioning (P = .03 and P = .03, respectively). CONCLUSION: An association of TNF with memory, previously reported in patients after exposure to chemotherapy, was found prior to initiation of any treatment, including surgery. This association requires further investigation as sTNF-RII was not higher in cancer patients relative to control participants.

Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis.

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the premetastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients, and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the premetastatic niche. Mechanistically, cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase. In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that, by modifying glucose utilization by recipient premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.

Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women.

BACKGROUND: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies. METHODS: We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm. RESULTS: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2. CONCLUSIONS: Positive screens were more frequent when HE4 was included in the primary screen. IMPACT: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen.

Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis.

Cancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer.

Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer.

BACKGROUND: Human epididymis protein 4 (HE4) is approved for clinical use with CA125 to predict epithelial ovarian cancer in women with a pelvic mass or in remission after chemotherapy. Previously reported reference ranges for HE4 are inconsistent. METHODS: We report positivity thresholds yielding 90%, 95%, 98%, and 99% specificity for age-defined populations of healthy women for HE4, CA125, and Risk of Ovarian Malignancy Algorithm (ROMA), a weighted average of HE4 and CA125. HE4 and CA125 were measured in 1,780 samples from 778 healthy women aged >25 years with a documented deleterious mutation, or aged >35 years with a significant family history. Effects on marker levels of a woman's age, ethnicity, and epidemiologic characteristics were estimated, as were the population-specific means, variances, and within- and between-woman variances used to generate longitudinal screening algorithms for these markers. RESULTS: CA125 levels were lower with Black ethnicity (P = 0.008). Smoking was associated with higher HE4 (P = 0.007) and ROMA (P < 0.019). Continuous oral contraceptive use decreased levels of CA125 (P = 0.041), and ROMA (P = 0.12). CA125 was lower in women age ≥55, and HE4 increased with age (P < 0.01), particularly among women age ≥55. CONCLUSIONS: Because of the strong effect of age on HE4, thresholds for HE4 are best defined for women of specific ages. Age-specific population thresholds for HE4 for 95% specificity ranged from 41.4 pmol/L for women age 30 to 82.1 pmol/L for women age 80. IMPACT: Incorporation of serial marker values from screening history reduces personalized thresholds for CA125 and HE4 but is inappropriate for ROMA.

De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer.

BACKGROUND: MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome. METHODS: The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers. RESULTS: More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients. CONCLUSIONS: Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.

BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPRETATION: EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

Progress in aromatase research and identification of key future directions.

The IX International Aromatase Conference focused upon key developments in research related to the aromatase enzyme that had occurred since the last meeting. A session took place at the conclusion of conference discussing key areas for future research and issues currently facing researchers in the field. While significant progress on understanding structural elements of the enzyme and regulatory mechanisms of both the gene and protein provides an excellent basis for development of improved aromatase inhibitors and exploration of the important problem of aromatase inhibitor resistance, significant challenges remain. Increasing the speed with which findings are translated into clinical practice and finding an appropriate balance between basic and translational research were identified as areas which require further attention before the next meeting in 2010.

Contralateral risk-reducing mastectomy in young breast cancer patients with and without genetic cancer risk assessment.

BACKGROUND: Decisions regarding contralateral risk-reducing mastectomy (CRRM) among women diagnosed with unilateral breast cancer can potentially be influenced by age at diagnosis and other factors. In this study, we examined the use of CRRM before versus after genetic cancer risk assessment (GCRA) in women diagnosed with breast cancer before age 50. METHODS: We conducted a retrospective analysis of women with invasive breast cancer diagnosed before age 50 who were seen for GCRA between October 1996 and March 2005. Associations between the presence of generally accepted indications for risk-reducing surgery among women who had CRRM and the timing of GCRA were examined. RESULTS: The cohort included 378 women, of whom 57 had CRRM pre-GCRA and 45 had CRRM post-GCRA after a median follow-up of 26 months. Women who had CRRM pre-GCRA were more likely to not have a generally accepted indication for the procedure than those who did after GCRA (odds ratio [OR] 5.3, 95% confidence interval [95% CI] 1.6-17.8, P = .007). Women diagnosed with breast cancer before BRCA genetic testing became clinically available (1997) were more likely to have had CRRM pre-GCRA than those who were diagnosed more recently (OR 2.9, 95% CI 1.6-5.2, P = .0003). CONCLUSION: When personal and family history was carefully examined, a substantial proportion of women seen in our clinic did not have a clear indication for CRRM. Decreased use of empiric CRRM among women diagnosed after 1997 may indicate increased awareness and use of GCRA. Thus, judicious application of GCRA may help focus use of surgical risk reduction measures to the most risk-appropriate patients.

Recruiting patients with breast cancer and their families to behavioral research in the post-HIPAA period.

PURPOSE/OBJECTIVES: To describe a process for, response rates of, and indicated interest in recruiting patients with breast cancer and their spouses and family members from a clinical setting into behavioral and psychiatric research studies since the Health Insurance Portability and Accountability Act (HIPAA) regulations have taken effect. DATA SOURCES: Published articles, books and book chapters, MEDLINE, government agency information and HIPAA regulatory Web sites, and survey data. DATA SYNTHESIS: Response rates among the three target groups--patients, spouses and partners, and female first-degree relatives--were 77%, 95%, and 88%, respectively. Interest was high in the three target groups, with 77%, 87%, and 65% of responding patients, spouses and partners, and female first-degree relatives, respectively. CONCLUSIONS: Taken together, these data indicate that high participation rates can be expected from patients with breast cancer and their families in clinical settings. IMPLICATIONS FOR NURSING: Regulations pose barriers to patient and family recruitment, but thoughtful systems actually can improve rates of recruitment.

Limited family structure and BRCA gene mutation status in single cases of breast cancer.

CONTEXT: An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. OBJECTIVE: To determine if BRCA gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. DESIGN, SETTING, AND PARTICIPANTS: A total of 1543 women seen at US high-risk clinics for genetic cancer risk assessment and BRCA gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. MAIN OUTCOME MEASURE: The main outcome measure was whether family structure, assessed from multigenerational pedigrees, predicts BRCA gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were generated. RESULTS: Family structure was limited in 153 cases (50%). BRCA gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. CONCLUSIONS: Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.

If we build it ... will they come?--establishing a cancer genetics services clinic for an underserved predominantly Latina cohort.

BACKGROUND: Cancer genetic counseling and testing is a standard of care option for appropriate families and can identify individuals at increased risk prior to diagnosis, when prevention or detection strategies are most effective. Despite documented efficacy of cancer risk reduction in high-risk individuals, underserved and minority individuals have a disproportionate cancer burden and limited access to genetic counseling. METHODS: A needs assessment survey documented gaps in knowledge and interest in prevention. Satellite clinics were established at two indigent healthcare systems. Cancer genetics CME lectures were conducted and referral guidelines disseminated to clinicians who referred patients for counseling. RESULTS: An increase in clinician knowledge was demonstrated post-CME and reflected by quality referrals. Eighty-eight percent of patients kept their appointments. In the predominantly Latina(6) (n=77) clinic population, 71.4% were affected with cancer, and 17 mutation positive families were identified. Preliminary data shows a positive impact on patients' motivation and behavior. The majority has expressed satisfaction and reduction in anxiety. CONCLUSIONS: This study demonstrates feasibility and acceptability of cancer genetics services in this population, suggesting the potential to reduce cancer morbidity in underserved, high-risk families.

Mammographic density correlation with Gail model breast cancer risk estimates and component risk factors.

BACKGROUND: The Gail model is a validated breast cancer risk assessment tool that is primarily based on nonmodifiable breast cancer risk factors. Conversely, mammographic breast density is strongly correlated with breast cancer risk and responds to risk-modifying interventions. The purpose of our study was to correlate mammographic density with breast cancer risk as calculated by the Gail model and to examine the relative association of each of the model covariates to mammographic density. METHODS: The study included 99 participants of the National Surgical Breast and Bowel Project P-1 trial, ages 36 to 74 years, all of whom had a mammogram and Gail model risk estimates done upon trial entry. Baseline mammograms were retrieved and digitized, and mammographic density was assessed by both subjective and computer-assisted objective measures. RESULTS: Mammographic density was 2-fold higher in women with a >15% lifetime risk of breast cancer compared with those with <15% risk, by all density assessment methods. This was equivalent to a 3% to 6% increase in density per 10% increase in risk. Gail model covariates that measured benign or premalignant breast tissue changes accounted for the majority (41%) of the relationship with increased mammographic density. Seven percent of density was not explained by risk factors included in the Gail model. CONCLUSIONS: The Gail model does not fully account for the association between breast density and calculated breast cancer risk. Because mammographic density is a modifiable marker, development of a breast cancer risk assessment tool that includes mammographic density could be beneficial for assessing individual risk.