Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.

Background: Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period. Methods: Patients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States). Results: Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score ≥3]; 61.1% Ki67 expression low (<14% positive cells); using immunohistochemistry (IHC) surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0.0-23.8) for all, 7.2 years (0.0-23.2), for M0, 2.6 years (0.0-12.7) for M1 patients. A significant improvement over time was observed in age-corrected BC mortality. BC-specific-mortality was higher for men younger than 50 years. Better overall (OS) and recurrence-free survival (RFS) were observed for highly ER+ (P = 0.001), highly PR+ (P = 0.002), highly AR+ disease (P = 0.019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions: Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity-breast cancer link.

BACKGROUND/OBJECTIVES: Obesity (body mass index (BMI)⩾30 kg m-2) is associated with an increased risk of estrogen-dependent breast cancer after menopause. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are elevated in breast tissue of obese women. Recently, the regulation of aromatase by the p53-hypoxia-inducible factor-1α (HIF1α)/pyruvate kinase M2 (PKM2) axis was characterized in adipose stromal cells (ASCs) of women with Li-Fraumeni Syndrome, a hereditary cancer syndrome that predisposes to estrogen-dependent breast cancer. The current study aimed to determine whether stimulation of aromatase by obesity-associated adipokine leptin involves the regulation of the p53-HIF1α/PKM2 axis. SUBJECTS/METHODS: Human breast ASCs were used to characterize the p53-HIF1α/PKM2-aromatase axis in response to leptin. The effect of pharmacological or genetic modulation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), p53, Aha1, Hsp90, HIF1α and PKM2 on aromatase promoter activity, expression and enzyme activity was examined. Semiquantitative immunofluorescence and confocal imaging were used to assess ASC-specific protein expression in formalin-fixed paraffin-embedded tissue sections of breast of women and mammary tissue of mice following a low-fat (LF) or high-fat (HF) diet for 17 weeks. RESULTS: Leptin-mediated induction of aromatase was dependent on PKC/MAPK signaling and the suppression of p53. This, in turn, was associated with an increase in Aha1 protein expression, activation of Hsp90 and the stabilization of HIF1α and PKM2, known stimulators of aromatase expression. Consistent with these findings, ASC-specific immunoreactivity for p53 was inversely associated with BMI in breast tissue, while HIF1α, PKM2 and aromatase were positively correlated with BMI. In mice, HF feeding was associated with significantly lower p53 ASC-specific immunoreactivity compared with LF feeding, while immunoreactivity for HIF1α, PKM2 and aromatase were significantly higher. CONCLUSIONS: Overall, findings demonstrate a novel mechanism for the obesity-associated increase in aromatase in ASCs of the breast and support the study of lifestyle interventions, including weight management, which may reduce breast cancer risk via effects on this pathway.

Research needs in breast cancer.

New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life.

Risk of acute myeloid leukemia and myelodysplastic syndrome among older women receiving anthracycline-based adjuvant chemotherapy for breast cancer on Modern Cooperative Group Trials (Alliance A151511).

PURPOSE: We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials with >90 months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines. METHODS: We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65 years; separately for ≥70 vs. <70 years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS. RESULTS: On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML [0.3%], 17 MDS [0.2%]); 83% of events occurred within 5 years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio [HR] for age ≥65 [vs. <65] = 3.13, 95% confidence interval [CI] 1.18-8.33; HR for anthracycline receipt [vs. no anthracycline] = 5.16, 95% CI 1.47-18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS. CONCLUSIONS: We observed an increased risk for AML/MDS for older patients and those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.

Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer: overall survival and updated progression-free survival results from a phase II study.

We previously reported progression-free survival (PFS) results on a phase II trial of weekly paclitaxel, trastuzumab, and pertuzumab in patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer (MBC) treated in the first- and second-line setting. Here, we report results for overall survival (OS) and updated PFS after an additional year of follow-up. Patients with HER2-positive MBC with 0-1 prior treatment were eligible. Treatment consisted of paclitaxel (80 mg/m(2)) weekly, and trastuzumab (loading dose 8 mg/kg â†’ 6 mg/kg) and pertuzumab (loading dose 840 mg â†’ 420 mg) every 3 weeks, all given intravenously. Primary endpoint was 6-month PFS. Secondary endpoints included median PFS, 6-month and median OS. Evaluable patients received at least one full dose of treatment. From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of July 1, 2015, the median follow-up was 33 months (range 3-49 months; 67 patients were evaluable for efficacy). The median OS was 44 months (95 % CI 37.5-NR) overall and 44 months (95 % CI 38.3-NR) and 37.5 months (95 % CI 30.3-NR) for patients with 0 and 1 prior metastatic treatment, respectively; 6-month OS was 98 % (95 % CI 90-1). The 6-month PFS was 86 % (95 % CI 75-93) overall and 89 % (95 % CI 76-95) and 78 % (95 % CI 51-91) for patients with 0 and 1 prior therapy, respectively; and median PFS was 21.4 months (95 % CI 14.1-NR) overall and 25.7 months (95 % CI 14.1-NR) and 16.9 months (95 % CI 8.5-NR) for patients with 0-1 prior treatment, respectively. Treatment was well tolerated. Updated analysis demonstrates that weekly paclitaxel, when added to trastuzumab and pertuzumab, is associated with a favorable OS and PFS and offers an alternative to docetaxel-based therapy. http://www.ClinicalTrials.gov NCT0127604.

Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signalling in women with hormone receptor-negative breast cancer.

BACKGROUND: Observational and experimental data support a potential breast cancer chemopreventive effect of green tea. METHODS: We conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I-III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers. RESULTS: From July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (-12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers. CONCLUSIONS: Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.

EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial.

BACKGROUND: Epidermal growth factor receptor (EGFR) has been hypothesised to modulate the effectiveness of anti-HER2 therapy. We used a standardised, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in the North Central Cancer Treatment Group (NCCTG) N9831 trial. METHODS: Tissue microarrays were constructed that allowed analysis of 1365 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) and chemotherapy with concurrent trastuzumab (Arm C). Measurement of EGFR was performed using the EGFR antibody, D38B1, on the fluorescence-based AQUA platform. The result was validated using an independent retrospective metastatic breast cancer cohort (n=130). RESULTS: Epidermal growth factor receptor assessed as a continuous (logarithmic transformed) variable shows an association with disease-free survival in Arm C (P=0.009) but not in Arm A or B. High EGFR expression was associated with worse outcome (Hazard ratio (HR)=2.15; 95% CI 1.28-3.60, P=0.004). Validation in a Greek metastatic breast cancer cohort showed an HR associated with high EGFR expression of 1.92 (P=0.0073). CONCLUSIONS: High expression of EGFR appears to be associated with decreased benefit from adjuvant concurrent trastuzumab. Since other treatment options exist for HER2-driven tumours, further validation of these data may select patients for alternative or additive therapy.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS: Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS: The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer.

BACKGROUND: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). RESULTS: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. CLINICAL TRIAL NUMBER: NCT00294996.

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

Paclitaxel efficacy and toxicity in older women with metastatic breast cancer: combined analysis of CALGB 9342 and 9840.

BACKGROUND: Two Cancer and Leukemia Group B (CALGB) studies were utilized to determine the efficacy and tolerability of paclitaxel (Taxol) in older patients with metastatic breast cancer. PATIENTS AND METHODS: CALGB 9840 evaluated weekly paclitaxel (80 mg/m(2)) versus paclitaxel every 3 weeks (175 mg/m(2)); CALGB 9342 evaluated three doses of paclitaxel as follows: 175, 210 and 250 mg/m(2) each over 3 h every 3 weeks. Of the 1048 patients, paclitaxel was used first line in 57%. The groups: (i) <55 years (45%), (ii) 55-64 years (29%), and (iii) ≥65 years (26%). RESULTS: Tumor response was also similar among age groups. First-line therapy (P = 0.0001) and better performance status (PS) (P = 0.018) were significantly related to higher response. Age did not significantly relate to overall survival (OS) or progression-free survival (PFS). First-line therapy, better PS, estrogen receptor positive status and a fewer number of metastatic sites were significantly related to improved OS and PFS. The grade ≥3 toxic effects that increased linearly with age were leucopenia (P = 0.0099), granulocytopenia (P = 0.022), anorexia (P = 0.028), bilirubin elevation (P = 0.0035) and neurotoxicity (P < 0.0001). Patients over 65 years receiving second-line therapy had the shortest time to neurotoxicity. CONCLUSIONS: Older women with breast cancer derive similar efficacy from treatment with paclitaxel as younger women. Older women are at increased risk for specific toxic effects.

The sequential use of endocrine treatment for advanced breast cancer: where are we?

BACKGROUND: Hormone receptor-positive advanced breast cancer is an increasing health burden. Although endocrine therapies are recognised as the most beneficial treatments for patients with hormone receptor-positive advanced breast cancer, the optimal sequence of these agents is currently undetermined. METHODS: We reviewed the available data on randomised controlled trials (RCTs) of endocrine therapies in this treatment setting with particular focus on RCTs reported over the last 15 years that were designed based on power calculations on primary end points. RESULTS: In this paper, data are reviewed in postmenopausal patients for the use of tamoxifen, aromatase inhibitors and fulvestrant. We also consider the available data on endocrine crossover studies and endocrine therapy in combination with chemotherapy or growth factor therapies. Treatment options for premenopausal patients and those with estrogen receptor-/human epidermal growth factor receptor 2-positive tumours are also evaluated. CONCLUSION: We present the level of evidence available for each endocrine agent based on its efficacy in advanced breast cancer and a diagram of possible treatment pathways.

Persistence, adherence, and toxicity with oral CMF in older women with early-stage breast cancer (Adherence Companion Study 60104 for CALGB 49907).

BACKGROUND: Cyclophosphamide-methotrexate-5-fluorouracil (CMF) is often selected as adjuvant chemotherapy for older patients with early-stage breast cancer due to perceived superior tolerability. We sought to measure persistence with CMF, adherence to oral cyclophosphamide, and the association of these with toxic effects. PATIENTS AND METHODS: CALGB 49907 was a randomized trial comparing standard chemotherapy (CMF or AC, provider/patient choice) with capecitabine in patients aged ≥65 with stage I-IIIB breast cancer. Those randomized to standard therapy and choosing CMF were prescribed oral cyclophosphamide 100 mg/m(2) for 14 consecutive days in six 28-day cycles. Persistence was defined as being prescribed six cycles of at least one of the three CMF drugs. Adherence was the number of cyclophosphamide doses that women reported they had taken divided by the number prescribed. Persistence and adherence were based on case report forms and medication calendars. RESULTS: Of 317 randomized to standard chemotherapy, 133 received CMF. Median age was 73 (range 65-88). Seventy-one percent submitted at least one medication calendar; 65% persisted with CMF. Non-persistence was associated with node negativity (P = 0.019), febrile neutropenia (P = 0.002), and fatigue (P = 0.044). Average adherence was 97% during prescribed cycles. CONCLUSIONS: Self-reported adherence to cyclophosphamide was high, but persistence was lower, which may be attributable to toxic effects.

A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer.

BACKGROUND: SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study. PATIENTS AND METHODS: Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m(2) was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme. RESULTS: Fifteen patients enrolled (median age 54 years, range 35-74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70-120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease. CONCLUSION: In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.

Breast carcinoma with brain metastases: clinical analysis and immunoprofile on tissue microarrays.

BACKGROUND: Development of brain metastasis in patients with breast carcinoma correlates with poor outcome. Identification of tumor characteristics associated with breast cancer brain metastases (BCBM) could help identify patients at risk. PATIENTS AND METHODS: We studied 209 patients with BCBM. We evaluated a panel of proteins relevant to the biology of breast carcinoma on tissue microarrays of 133 primary tumors and 56 BCBM, including paired samples from 43 patients, and correlated the findings with the clinical outcome. RESULTS: The median survival after BCBM diagnosis was 19 months (95% confidence interval, 13-23 months). Patients presenting with solitary metastasis had a significantly longer median survival than those with multiple lesions (25 versus 11 months, P ≤ 0.0001). We found no significant discordance in the expression of tested markers, but identified a possible association between the expression of basal cytokeratin CK5/6 in the primary carcinoma and the development of multiple rather than solitary brain metastases. CONCLUSIONS: Expression of antigens commonly associated with breast carcinoma does not differ significantly between the primary tumor and the corresponding brain metastases. Although no specific immunoprofile identifies breast carcinomas that develop brain metastases, we observed a possible association between CK5/6 expression in the primary tumor and multiple versus solitary BCBM.

Relative contributions of BRCA1 and BRCA2 mutations to "triple-negative" breast cancer in Ashkenazi Women.

Approximately 10% of Ashkenazi Jewish (AJ) women with breast cancer (BC) carry a founder mutation in BRCA1 or BRCA2. There is an association between BRCA1 mutations and "triple-negative" breast cancer (TNBC) [estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative]. We sought to determine the predictive value of the TNBC phenotype for the presence of a BRCA mutation in AJ women ascertained without respect to family history. DNA samples were collected between 8/2000 and 6/2004 from a prevalent cohort of unselected AJ women with breast cancer (median age at diagnosis 56 years). Samples (n = 451) were genotyped for AJ founder mutations. 352 (78.0%) cancers were ER positive, 254 (56.3%) PR positive, and 91 (20.2%) ER negative/PR negative. 63 (14.0%) cancers were HER2 positive (immunohistochemistry 3+ or FISH >2.2). TNBC was observed in 64 patients (14.2%). Founder mutations were detected in 48 samples (10.6%) including 25/64 TNBC (39.1%; 19 BRCA1, 6 BRCA2). Among TNBC patients with family history (FH) information, 6/15 (40%) mutations were found in women without breast or ovarian cancer in a close relative. The positive predictive value of TNBC for a BRCA1 mutation was 30% overall, 50% in women diagnosed<50 years, and 14% in women diagnosed ≥50. TNBC was significantly associated with detecting a mutation in either BRCA1 or BRCA2, but only 25/52 (48%) mutation-associated cancers were TNBC. The prevalence of BRCA founder mutations exceeds 50% in subsets of AJ women with TNBC. FH is an imperfect predictor of mutation status in this group. A significant number of mutation-associated TNBC are due to BRCA2.

Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women.

Several single nucleotide polymorphisms (SNPs) are associated with an increased risk of breast cancer. The clinical utility of genotyping individuals at these loci is not known. Subjects were 519 unaffected women without BRCA mutations. Gail, Claus, and IBIS models were used to estimate absolute breast cancer risks. Subjects were then genotyped at 15 independent risk loci. Published per-allele and genotype-specific odds ratios were used to calculate the composite cumulative genomic risk (CGR) for each subject. Affected age- and ethnicity-matched BRCA mutation-negative women were also genotyped as a comparison group for the calculation of discriminatory accuracy. The CGR was used to adjust absolute breast cancer risks calculated by Gail, Claus and IBIS models to determine the proportion of subjects whose recommendations for chemoprevention or MRI screening might be altered (reclassified) by such adjustment. Mean lifetime breast cancer risks calculated using the Gail, Claus, and IBIS models were 19.4, 13.0, and 17.7%, respectively. CGR did not correlate with breast cancer risk as calculated using any model. CGR was significantly higher in affected women (mean 3.35 vs. 3.12, P = 0.009). The discriminatory accuracy of the CGR alone was 0.55 (SE 0.019; P = 0.006). CGR adjustment of model-derived absolute risk estimates would have altered clinical recommendations for chemoprevention in 11-19% of subjects and for MRI screening in 8-32%. CGR has limited discriminatory accuracy. However, the use of a genomic risk term to adjust model-derived estimates has the potential to alter individual recommendations. These observations warrant investigation to evaluate the calibration of adjusted risk estimates.