Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Risk Management for BRCA1/BRCA2 mutation carriers without and with breast cancer.

PURPOSE OF REVIEW: We review the management for unaffected BRCA1/2 mutation carriers and the local management of early stage breast cancer. RECENT FINDINGS: For unaffected BRCA1/2 mutation carriers, surveillance includes annual magnetic resonance imaging (MRI) and mammogram (MG). Novel imaging modalities, including abbreviated protocol MRI, ultrafast/accelerated MRI, and contrast-enhanced digital mammography are being investigated. Risk reducing mastectomy (RRM) should be considered, and nipple-areolar sparing mastectomy (NSM) is now an option. Additionally, risk reducing salpingo-oophorectomy (RRSO) is strongly recommended as it reduces mortality.In BRCA1/2 mutation carriers with breast cancer, BCT is an appropriate treatment option but to reduce risk of second primary, mastectomy and contralateral risk-reducing mastectomy should be considered.

Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.

PURPOSE: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. METHODS: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. RESULTS: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. CONCLUSION: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination.

In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert(®) MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority.

Risk of cardiovascular adverse events from trastuzumab (Herceptin(®)) in elderly persons with breast cancer: a population-based study.

Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin (®) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox-proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab-associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66-75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.

A peer-led decision support intervention improves decision outcomes in black women with breast cancer.

Previous reports suggest that Black breast cancer patients receive less patient-centered cancer care than their White counterparts. Interventions to improve patient-centered care (PCC) in Black breast cancer patients are lacking. Seventy-six women with histologically confirmed breast cancer were recruited from the Washington, DC area. After a baseline telephone interview, women received an in-person decision support educational session led by a trained survivor coach. The coach used a culturally appropriate guidebook and decision-making model-TALK Back!(©) A follow-up assessment assessed participants' acceptability of the intervention and intermediate outcomes. After the intervention, participants reported increased: self-efficacy in communicating with providers (70 %) and self-efficacy in making treatment decisions (70 %). Compared to baseline scores, post-intervention communication with providers significantly increased (p= .000). This is the first outcome report of an intervention to facilitate PCC in Black breast cancer patients. Testing this intervention using RCTs or similar designs will be important next steps.

Patterns of fatal machine rollovers in Canadian agriculture.

INTRODUCTION: Our objectives were to examine the activities and circumstances associated with agricultural machine-related rollover fatalities. METHODS: We identified agricultural machine rollover fatalities recorded by the Canadian Agricultural Injury Surveillance Program (CAISP) in 1990-2005. We determined sideways and backwards rollovers by year, age and sex of the victims, agricultural season, machine type, and the activity, circumstances and location of the injury event. RESULTS: The annual rate of rollover fatalities in Canada was 9.1 per 100,000 farm operations. Rollover fatalities decreased to 30% of baseline over the 16-year study period (p = .004). Fatal rollovers most often occurred among men aged 50-69 years and 60-79 years for sideways and backwards rollovers, respectively. DISCUSSION: Sideways rollovers occur when driving across an incline or at the edge of a ditch bordering a roadway or field. Backwards rollovers occur when driving up an incline, towing or extracting stuck machines, pulling stumps or trees, and towing implements or logs. Primary prevention programs for rollover injuries should target these identified patterns of injury.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809.

BACKGROUND: Chemotherapy-induced ovarian failure (CIOF) is a frequent side-effect of adjuvant chemotherapy that results in rapid bone loss. We hypothesised that zoledronic acid (ZA), a third-generation amino bisphosphonate, would prevent bone loss in premenopausal women who developed CIOF. METHODS: Women (439) were randomised to intravenous (i.v.) ZA 4 mg every 3 months for 2 years starting within 1-3 months after randomization (arm A) or 1 year after randomization (arm B, controls). CIOF was prospectively defined as ≥ 3 months of amenorrhoea, follicle-stimulating hormone (FSH) ≥ 30 MIU/ml and non-pregnant at 1 year. The primary end-point was the percentage change in bone mineral density (BMD) in the lumbar spine (LS) from baseline to 12 months in the ZA and in control groups in women who developed CIOF; the secondary end-point was BMD in LS at 3 years in all randomised women. FINDINGS: One hundred and fifty (56%) met the definition of CIOF at 1 year. Overall, grade 3 toxicities of ZA were fatigue (1%) arthralgias (21%) and pain (84%). The median percent change (interquartile range, IQR) at 1 year was +1.2% (-0.5% to +2.8%) and -6.7% (-9.7% to -2.9%) p<0.001 and at 3 years was +1.0% (-1.6% to +5.2%) and -0.5% (-3.7% to +3.2%) p=0.019 in arms A and B, respectively. INTERPRETATION: ZA every 3 months is well tolerated and prevents rapid bone loss in premenopausal women that develop CIOF. Giving ZA with rather than 1 year after the start of adjuvant chemotherapy is the preferred sequence to prevent bone loss.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Evaluation of WLBU2 peptide and 3-O-octyl-sn-glycerol lipid as active ingredients for a topical microbicide formulation targeting Chlamydia trachomatis.

Topical microbicides for prevention of sexually transmitted diseases (STDs) would be especially useful for women who are not able to persuade their partner(s) to take precautions. Many topical microbicides are in various stages of development, based on a variety of active ingredients. We investigated the in vitro activity of an engineered antimicrobial peptide (WLBU2) and a lipid (3-O-octyl-sn-glycerol [3-OG]) which could potentially be used as active ingredients in such a product. Using commercially available cytotoxicity reagents [Alamar Blue, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and lactate dehydrogenase (LDH)], we first determined the toxicity of WLBU2 and 3-OG to the host cells in our assay procedure and excluded toxic concentrations from further testing. To determine activity against Chlamydia trachomatis, we used an assay previously developed by our laboratory in which chlamydial elementary bodies (EBs) were exposed to microbicides prior to contact with epithelial cells: the minimum (microbi)cidal concentration (MCC) assay. To further simulate conditions of transmission, we carried out the same assay in the presence of a simulated vaginal fluid, a simulated seminal fluid, human serum albumin, and a range of pH values which might be found in the human vagina at the time of exposure. Last, we tested WLBU2 and 3-OG in combination to determine if adding them together resulted in synergistic activity. We found that WLBU2 and 3-OG both have excellent activity in vitro against C. trachomatis and significantly more activity when added together. The simulated fluids reduced activity, but the synergy seen is good evidence that they would be effective when combined in a microbicide formulation.

BRCA1 in hormonal carcinogenesis: basic and clinical research.

The breast and ovarian cancer susceptibility gene-1 (BRCA1) located on chromosome 17q21 encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. The observation that most BRCA1 mutant breast cancers are hormone receptor negative has led some to question whether hormonal factors contribute to the etiology of BRCA1-mutant breast cancers. Nevertheless, the caretaker function of BRCA1 is a generic one and does not explain why BRCA1 mutations confer a specific risk for tumor types that are hormone-responsive or that hormonal factors contribute to the etiology, including those of the breast, uterus, cervix, and prostate. An accumulating body of research indicates that in addition to its well-established roles in regulation of the DNA damage response, the BRCA1 protein interacts with steroid hormone receptors (estrogen receptor (ER-alpha) and androgen receptor (AR)) and regulates their activity, inhibiting ER-alpha activity and stimulating AR activity. The ability of BRCA1 to regulate steroid hormone action is consistent with clinical-epidemiological research suggesting that: (i) hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers; and (ii) the spectrum of risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that observed in the general population. These data suggest a model for BRCA1 carcinogenesis in which genomic instability leads to the initiation of cancerous cell clones, while loss of normal restraint on hormonal stimulation of mammary epithelial cell proliferation allows amplification of these pre-existing clones. Further research will be required to substantiate this hypothesis.

Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. METHODS: We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 280]), year of birth (+/-2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. RESULTS: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P(trend)<.001). Women with BRCA1 mutations who breast-fed for more than 1 year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83). CONCLUSIONS: Women with deleterious BRCA1 mutations who breast-fed for a cumulative total of more than 1 year had a statistically significantly reduced risk of breast cancer.

Impact of educational print materials on knowledge, attitudes, and interest in BRCA1/BRCA2: testing among Ashkenazi Jewish women.

BACKGROUND: The recent identification of several BRCA1/BRCA2 founder mutations among Ashkenazi Jewish individuals has led to increased salience of BRCA1/BRCA2 testing for Jewish individuals. Little is known about interest in BRCA1/BRCA2 testing among Ashkenazi Jews from the general population. Furthermore, previous research has not generally evaluated the impact of education on interest in testing among individuals from the general population. The goal of the current study was to examine whether a brief educational booklet regarding BRCA1/BRCA2 testing would influence knowledge, attitudes, and interest in testing among Ashkenazi Jewish women from the general population. METHODS: After a baseline telephone interview, participants were randomized to receive either genetic testing educational print materials (n = 195 women) or general breast cancer education control materials (n = 196 women). One month after receiving these materials, the authors reassessed knowledge, attitudes, and interest in BRCA1/BRCA2 gene testing. RESULTS: Relative to the breast cancer education control materials, the genetic testing education materials led to increased knowledge, increased perception of the risks and limitations of testing, and decreased interest in obtaining a BRCA1/BRCA2 mutation test. CONCLUSIONS: These data indicate that preliminary print education can be used to educate low-risk individuals about BRCA1/BRCA2 genetic testing. This approach may be used to educate low-risk individuals about the benefits and risks/limitations of BRCA1/BRCA2 testing, so that they can make informed decisions about whether to pursue genetic counseling.

Human airway smooth muscle expresses 7 isoforms of adenylyl cyclase: a dominant role for isoform V.

Adenylyl cyclases are a nine-member family of differentially regulated enzymes responsible for the synthesis of cAMP. cAMP is an important second messenger that contributes to the regulation of airway smooth muscle tone. However, little is known regarding the expression and regulation of adenylyl cyclase isoforms in airway smooth muscle cells. Nondegenerate specific primers were designed for all nine known isoforms of human adenylyl cyclase. RT-PCR experiments were performed using total RNA extracted from whole human brain (positive control), whole rat brain (negative control), whole human trachea, human airway smooth muscle, and primary cultures of human airway smooth muscle cells. Seven of the nine known isoforms of adenylyl cyclase (isoforms I, III-VII, and IX) were expressed at the mRNA level in both human airway smooth muscle and primary cultures of human airway smooth muscle cells. Immunoblot and adenylyl cyclase functional assay indicated that isoform V is likely among the functionally predominant isoforms of adenylyl cyclase in human airway smooth muscle. These results suggest that multiple isoforms of adenylyl cyclase enzymes are coexpressed in human airway smooth muscle cells and that isoform V is among the functionally important isoforms.

Effects of coping style and BRCA1 and BRCA2 test results on anxiety among women participating in genetic counseling and testing for breast and ovarian cancer risk.

Using the monitoring process model (MPM), the authors examined the immediate effects of coping style and test results on the psychological distress of women at increased risk for breast and/or ovarian cancers. Cases selected for analysis were 107 probands and relatives of positive probands participating in genetic counseling and testing for heritable cancer risk. Specifically, the authors explored the relationships among coping style (high and low monitoring), test results (BRCA1 and BRCA2 mutation carrier and noncarrier status), and psychological distress (state anxiety). Consistent with the MPM, higher monitoring was associated with greater psychological distress while anticipating genetic test results. After test results were disclosed, greater distress was associated with testing positive for a mutation. The implications of the findings for breast and ovarian cancer patients are discussed.

BRCA1/2 testing: complex themes in result interpretation.

Since the cloning of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become more widespread. However, interpretation of test results is not always straightforward. To illustrate this point, five vignettes adapted from actual cases are presented. As these cases demonstrate, in many high-risk families, a deleterious mutation in BRCA1 or BRCA2 is not identified in an affected proband. There are several potential explanations for such a finding, namely that an undetected mutation in BRCA1 or BRCA2 may exist, or there could be a mutation in a rare or undiscovered gene. In addition, the possibility that women with breast cancer represent sporadic cases within hereditary cancer families must also be considered. Finally, the occurrence of BRCA1/2 variants of uncertain significance, often missense mutations, further complicates the risk assessment. In some of these instances, extending testing to relatives can be helpful to clarify results. When hereditary breast cancer cannot be ruled out, individuals may still be at increased risk for cancer and therefore need to obtain appropriate surveillance. The process of genetic counseling is critical both before and after testing to ensure that patients understand the potential medical and psychosocial implications of testing and are aware of available options and resources. A multidisciplinary approach to service delivery, which includes clinicians in genetics and oncology, can facilitate patients' decision making and provide continued access to information and support.