Time to reconsider subcutaneous mastectomy for breast-cancer prevention?

Genetic testing for women at increased risk of developing breast cancer has moved from the research setting to become part of established clinical practice. By testing for inherited mutations in BRCA1 and BRCA2, we are identifying more and more women who have an 80% or more lifetime risk of developing breast cancer. Since the discovery of BRCA1 in 1994, several clinical studies have led to strategies for reducing the risk of developing breast cancer, including prophylactic mastectomy, prophylactic oophorectomy, and preventive tamoxifen. We believe that in 2005, all prophylactic options, including subcutaneous and total mastectomy should be discussed and made available to women who find themselves unfortunate enough to have inherited a BRCA mutation.     

Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.     

Sociocultural predictors of breast cancer risk perceptions in African American breast cancer survivors.

Although African American breast cancer survivors are at increased risk for developing breast cancer again, empirical data are not available on breast cancer risk perceptions in these women. This study characterized perceived risk of developing breast cancer in African American breast cancer survivors at risk for having a BRCA1 or BRCA1 (BRCA1/2) mutation and identified factors having significant independent associations with risk perceptions. Participants were 95 African American breast cancer survivors at an increased risk for having a BRCA1/2 mutation. Risk perceptions and sociodemographic, clinical, treatment, and sociocultural factors were collected during a structured telephone interview. Most women reported that they had the same or lower risk of developing breast cancer again compared with other women (53%); however, a substantial minority of women (47%) reported that they had a higher or much higher risk. Factors having significant independent associations with heightened risk perceptions included having a >or=10% prior probability of having a BRCA1/2 mutation [odds ratio (OR), 2.91; 95% confidence interval (95% CI), 1.09-7.72; P = 0.03] and more years of formal education (OR, 2.74; 95% CI, 1.02-7.36; P = 0.05). In addition, women who thought about the past a lot were three times more likely to report heightened risk perceptions compared with those who did not think about the past a lot (OR, 3.72; 95% CI, 1.45-9.57; P = 0.01). These results suggest that it may be important to ensure adequate risk comprehension among African American women as part of genetic counseling for inherited breast-ovarian cancer risk. Discussion of risk perceptions within the context of existing beliefs and values may facilitate this process.     

Individualized preventive and therapeutic management of hereditary breast ovarian cancer syndrome

Life-saving, risk-reducing medical interventions are required for women with a BRCA1/2 mutation. Interventions comprise a four-stage approach that involves risk assessment, genetic counseling, gene-mutation analysis and medical intervention strategies. Genetic counseling should be offered at specialized familial breast-cancer clinics and gene-mutation analysis should be recommended on the basis of personal and family-history-based risk criteria. Prophylactic bilateral salpingo-oophorectomy appears to offer the optimal benefit-risk ratio compared with prophylactic bilateral mastectomy, chemoprevention, or intensified surveillance. Tamoxifen is an alternative approach only for BRCA2 mutation carriers. The comprehensive, clinical decision-making Ioannina algorithm provided here can facilitate the complex preventive strategic approach. Newly diagnosed BRCA1/2 carriers might benefit from extensive surgery and a specific pharmacological treatment, but data to support this strategy are limited. Microarray gene-expression studies show that breast tumors from BRCA1 carriers are predominantly of basal subtype (i.e. triple negative) and BRCA2 carriers are of luminal subtype (i.e. estrogen-receptor-positive). Although optimum management of women with familial susceptibility to breast and ovarian cancer has not yet been prospectively validated, data indicate substantial benefits when an individualized evidence-based prevention strategy is provided by an experienced team.     

Estimates of the likely prophylactic effect of tamoxifen in women with high risk BRCA1 and BRCA2 mutations

The development of breast cancer control strategies in women at high genetic risk of breast cancer is an important issue. The likely benefit of chemopreventive approaches is of particular interest. Tamoxifen tends to be more effective in both prevention and treatment of oestrogen receptor positive tumours than oestrogen receptor negative. In this study, we combine the oestrogen-receptor specific effects of tamoxifen from randomized preventive or therapeutic trials with the oestrogen receptor status of tumours in BRCA1 and BRCA2 mutation positive women from published tumour surveys to obtain estimates of the likely effect of tamoxifen administration in mutation carriers. We used a simple two-stage procedure to estimate the benefit as a weighted average of the effect on oestrogen receptor positive tumours and oestrogen receptor negative, and using a more complex hierarchical modelling approach. Using the simple procedure and deriving the estimates of benefit from both primary prevention and therapeutic trials, we obtain an estimated reduction in risk of breast cancer from administration of tamoxifen in BRCA1 mutation positive women of 13% (RR=0.87, 95% CI 0.68--1.11). The corresponding estimated reduction in BRCA2 mutation positive women was 27% (RR=0.73, 95% CI 0.59--0.90). Using the more complex models gave essentially the same results. Using only the primary prevention trials gave smaller estimates of benefit in BRCA1 carriers but larger estimates in BRCA2, in both cases with wider confidence intervals. The benefit of prophylactic use of tamoxifen in BRCA1 mutation carriers is likely to be modest, and the effect in BRCA2 mutation carriers somewhat greater.     

Risk of breast and ovarian cancer in women with strong family histories

Assessing the risk of breast and ovarian cancer starts with obtaining a complete and accurate family history. This can reveal evidence of inherited cancer risk. The highest risk of cancer is associated with germ-line abnormalities in several genes, including BRCA1, BRCA2, and TP53. Moderate-risk genes associated with syndromes that are inherited in an autosomal dominant pattern (such as Cowden's disease, hereditary non-polyposis colorectal cancer, Muir-Torre syndrome, and Peutz-Jeghers syndrome) exhibit lower penetrance and thus less risk of breast and/or ovarian cancer. Low-risk genes likely require significant environmental exposure, and although they are associated with the lowest risk of cancer, they account for more cancer than high- and moderate-risk genes. Lifetime risks for breast or ovarian cancer can be estimated. The Gail and Claus models, the more widely utilized models for calculation of lifetime breast cancer risk, are discussed. Models are also available for determining the likelihood of finding a BRCA1/2 mutation (the BRCAPRO and Myriad models). Appropriate candidates for testing include affected individuals who are most likely to have a hereditary form of cancer. Testing should proceed only after a thorough discussion of the risks, benefits, and limitations of testing. Risk-reducing options are available to women with a strong family history of breast and ovarian cancer. These options include high-risk screening, chemoprevention, and prophylactic surgery.     

Recognition and management of hereditary breast cancer syndromes

Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.     

Refining BRCA1 and BRCA2 penetrance estimates in the clinic

Genetic testing for mutations in BRCA1 and BRCA2 can provide important information to women and help guide clinical management decisions regarding interventions such as oophorectomy to reduce cancer risk. However, variability exists in risks of breast and ovarian cancer in individual BRCA1 and BRCA2 mutation carriers, with potential contributing factors including genotype-phenotype correlations, modifier genes, environmental and reproductive exposures, and the impact of interventions. Ultimately, the clinical goal is to provide individualized assessment of breast and ovarian cancer risk to BRCA1 and BRCA2 mutation carriers accounting for these variables to aid decision-making. This article discusses factors affecting the penetrance of cancer risks in BRCA1/2 mutation carriers.     

Clinical management of BRCA1- and BRCA2-associated breast cancer

The recent discovery of the breast cancer-associated genes BRCA1 and BRCA2 has changed the clinical care provided to women at high risk of breast cancer. We will review what is currently known about the clinical management of patients who bear (or are suspected of bearing) mutations in either of these two genes. The issues related to establishing a diagnosis of inherited breast cancer, deciding which women are candidates for testing, the limitations of testing, and the predictive power of these tests are addressed. The prognostic features of cancers associated with a BRCA1 and BRCA2 mutation are reviewed. Further, guidelines for prophylaxis of women with a BRCA1 or BRCA2 mutation are given and recommendations are made for the care of mutation carriers with cancer.     

Cancer prevention and screening practices among women at risk for hereditary breast and ovarian cancer after genetic counseling in the community setting

The context is that there are limited data regarding the management of women at risk for hereditary breast and ovarian cancer (HBOC) after genetic counseling in the community setting. The objective of the study is to examine the cancer screening and prevention behaviors among women with diverse risk factors for HBOC, counseled through a non-academic genetic counseling service. This study was designed as a retrospective telephone survey. A community/private-hospital based cancer genetic counseling service was setting. The patients studied were women, at least 21 years of age, who had undergone cancer genetic counseling with: (1) a ≥10% predicted likelihood of carrying a BRCA1/2 mutation; (2) a documented BRCA1/2 mutation. A 121-item telephone survey was intervened. Main outcome measures are (1) reason for referral, (2) genetic testing/results, and (3) screening and prevention behaviors. Sixty-nine women participated (31% response rate). Forty-nine (71%) respondents had a history of breast cancer. Forty-three women (62%) reported undergoing BRCA1/2 testing, of these, seven (16%) had a deleterious mutation; 32 (74%) received negative results and four (9%) had “inconclusive” findings. Among the seven with documented mutations; five had a personal history of breast cancer; none had a history of ovarian cancer; all had undergone bilateral salpingo-oophorectomy (BSO), while five (71%) had undergone bilateral mastectomy. Among those 62 respondents without a documented mutation, pretest likelihood of a BRCA1/2 mutation (based on established models) was as follows: 10–29% likelihood in 38 (61%); 30–59% likelihood in 16 (26%); and ≥60% likelihood in eight (13%). Of these, 16 (26%) had undergone bilateral mastectomy for treatment and/or risk-reduction while 20 (32%) had undergone BSO for risk-reduction or for “other reasons”. Almost all who had not undergone bilateral mastectomy were presenting for regular mammograms; fewer were undergoing regular breast MRI imaging. For those who had not undergone risk-reducing BSO; few were having CA-125 levels or transvaginal ultrasounds. Among those studied, the majority underwent genetic testing. A significant percentage elected to undergo risk-reducing mastectomy and BSO. Although prophylactic surgical decisions appeared to be largely influenced by BRCA mutation status, a number of women in the lower risk categories had undergone these procedures.     

Cancer risk reduction and reproductive concerns in female BRCA1/2 mutation carriers

BACKGROUND: Women with mutations in the BRCA1 or BRCA2 cancer susceptibility genes face unique choices regarding management of their high risk for breast and ovarian cancer that impact their reproductive options. In order to explore women's preferences for management of elevated cancer risk, we evaluated the decisions of BRCA1/2 mutation carriers about contraception, prophylactic surgery, and family planning. METHODS: An internet-based questionnaire assessing high-risk women's preferences about cancer risk management and reproductive options was designed, pilot-tested and administered electronically to 284 participants of an internet-based advocacy group for women with BRCA1/2 mutations. RESULTS: Two hundred and thirteen eligible participants completed the majority of the survey. Mean age was 34 years; 66% were BRCA1 mutation carriers and 34% were BRCA2 mutation carriers. Most women (92%) had used oral contraceptive pills. About 88% of responders reported frequent or extreme worry about transmitting the mutation to their children. Despite their high level of worry, few responders said they would likely consider using assisted reproduction technologies such as a pregnancy surrogate (3%), cryopreservation of oocytes or embryos (8%), or pre-implantation genetic diagnosis (PGD) to select embryos without BRCA1/2 mutations (13%). CONCLUSIONS: Although they expressed substantial concern about transmitting BRCA1/2 mutations to their children, only a minority of the high-risk women surveyed were likely to consider currently available assisted reproductive strategies. Further research is necessary to explore the risk management preferences of patients with inherited cancer predisposition, and to incorporate these preferences into clinical care.     

Evaluation and management of women with BRCA1/2 mutations

Genetic counseling and testing for susceptibility to breast and ovarian cancer is often an integral component of management for women with a personal and/or family history of these malignancies. In this article, we will briefly review the function and genetic epidemiology of the two major susceptibility genes, BRCA1 and BRCA2. We will then address approaches to risk assessment for women at high risk with respect to the probability that they harbor a deleterious mutation in one of these genes, and the likelihood that they will develop cancer if such a mutation is identified. The process of genetic counseling and testing is discussed, including a summary of the potential benefits, limitations, and risks of testing as well as a summary of test result interpretation. We conclude with a review and appraisal of the various options for breast and ovarian cancer risk reduction and screening options for women with a BRCA1 or BRCA2 mutation.     

Medical management of women with inherited predisposition to breast cancer: indications and procedures for mammographic screening

Women identified or suspected as carriers of mutations in BRCA1 or BRCA2 susceptibility genes have a high risk to develop an early breast cancer and thus, require appropriate management. Some consensus guidelines were provided for women at hereditary risk and two possible strategies of prevention are suggested: breast cancer screening and prophylactic surgery. We present the French recommendations for breast cancer surveillance and discuss the justification, indications and modalities of mammographic screening. Screening by annual mammography is recommended from age 30 years in experienced centers, in association with semi-annual clinical breast examination from age 20 years. These recommendations apply to women who were identified as carriers of a cancer-predisposing mutation of BRCA1 or BRCA2 genes. In families for whom any mutation of the two genes could be identified, the same modalities apply also to women with a higher probability than 25% of being a carrier. We present here an illustration of the calculation of such probabilities from two example-pedigrees.     

Probability estimation models for prediction of BRCA1 and BRCA2 mutation carriers: COS compares favourably with other models

Background Accurate risk assessment is essential to genetic counselling for a family history of cancer. Several empiric and computer-based risk assessment models have been developed to estimate a counselee's probability of being a carrier of mutation in BRCA1 and/or 2 genes, and to predict the risk of developing breast cancer. The COS model was developed from the better-known BRCAPro model to estimate risk of carriage of BRCA1 or 2 mutation. The COS model remains to be validated in a population discrete from that used for its development. Methods Four probability estimation models including COS, Manchester scoring system (MSS), BOADICEA and Tyrer-Cuzick (T-C) were applied to 275 Scottish families tested for BRCA1/2 mutations ascertained through regional genetics centres to ascertain models' sensitivity, specificity and accuracy. A subset of 130 families from Grampian (North and Northeast Scotland) was used to assess the models' ability to estimate the prevalence of BRCA1/2 mutation carriers. Sensitivity, specificity and ROC plots were used to ascertain models' individual performance, in terms of number of cancer cases, type of cancer and age of diagnosis of breast cancer. Results The COS and MSS models demonstrated the greatest sensitivities and area under ROC curves for the majority of family structures. They also showed the highest sensitivities (91-92%) and AUCs (76-78%) for the entire dataset overall. However, BOADICEA and T-C had the highest specificities for the majority of the family structures. BOADICEA and T-C generated the best estimates for the prevalence of mutations in the population; BOADICEA was more accurate for BRCA1 and T-C for BRCA2. Conclusion The COS and MSS models are the most effective models for use in clinical practice to select families for mutation analysis, but BOADICEA and T-C are more accurate for estimating mutation prevalence within a population.     

Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

INTRODUCTION: Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. METHODS: We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. RESULTS: Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). CONCLUSIONS: These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.     

Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature.

Major risks conferred by BRCA1 and BRCA2 in women are for cancers of the breast, ovary, fallopian tube, and peritoneum. Male carriers of mutations in BRCA1 or BRCA2 are also susceptible to cancer; however, their risks remain poorly understood and their optimal clinical management has not yet been defined. This article reviews studies that estimate risk associated with mutations in BRCA1 or BRCA2, with a focus on the cancer sites most relevant to men. Male BRCA1 mutation carriers are at increased risk of cancers of the prostate and breast. Evidence supporting increased susceptibility to colon cancer is limited. In contrast to women, who have a greater lifetime risk of cancer with mutations of the BRCA1 gene, BRCA2 is the more important gene for men. The spectrum of cancers is wide for BRCA2 and some studies report that the overall cancer risk for male BRCA2 carriers exceeds the risk for female carriers. In particular, the relative risk to male BRCA2 mutation carriers is high before age 65 years, largely attributable to breast, prostate, and pancreatic cancers. BRCA2 mutation carriers are also at risk of stomach cancer and melanoma (of the skin and eye). Additional research into risks to male BRCA1 or BRCA2 mutation carriers is necessary, specifically to determine the magnitude of excess cancer risk among BRCA2 carriers and to increase our understanding of the basis for the observed site-specificity in cancer development.     

Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case–control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20–0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1–4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32–0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44–1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.     

BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers.

Ninety-eight women ascertained from high-risk breast/ovarian cancer clinics with breast cancer reporting at least one other primary cancer in themselves or in a relative with breast cancer were compared with 99 women with breast cancer who reported a family history of breast cancer only. All DNA was screened for coding region mutations in BRCA1 and BRCA2 using heteroduplex analysis, followed by direct sequencing. Our data indicate that 42.9% of families reporting breast and any second nonbreast type of primary cancer in the same individual had a BRCA1 or BRCA2 mutation, as compared with the 12.1% of families reporting breast cancer only (P < 0.001). Among the 66 women reporting breast cancer and a nonovarian second primary cancer, 15 (22.7%) had mutations in BRCA1 or BRCA2 (P = 0.04). Among the 32 families where ovarian cancer was the second primary cancer, 27 (84.4%) had a mutation in BRCA1 or BRCA2 (P < 0.001). BRCA1 and BRCA2 mutations were twice as common in the presence of a reported second nonovarian cancer. These data suggest that the presence of multiple primary cancer of any kind may predict for an increased likelihood of finding a BRCA1 or BRCA2 mutation and supports previous studies suggesting that BRCA1 and BRCA2 mutations may be associated with an increased susceptibility to cancers other than breast and ovarian cancer.     

中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌风险的研究

背景与目的：BRCA1和BRCA2基因突变携带者终生患乳腺癌和卵巢癌的风险显著增高。通过遗传咨询,突变携带者可采取适当的措施来降低相应肿瘤的发生风险。目前,相关的报道几乎均为白种人,尚缺乏中国人群的资料。该研究旨在探索中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌的风险。方法：回顾20个经基因检测证实携带BRCA1或BRCA2致病性基因突变的汉族乳腺癌高风险家系。利用Kaplan-Meier生存分析法对女性BRCA1/2基因突变携带者单侧乳腺癌及对侧乳腺癌的累积发病风险进行估算。结果：BRCA1和BRCA2基因突变携带者70岁时单侧乳腺癌的累积发病风险(外显率)分别为67.2%(sx 0.100)和76.8%(sx 0.079)。与BRCA1不同的是,BRCA2基因突变携带者70岁后乳腺癌累积发病率继续增加,到80岁时达93.1%。BRCA1/2基因突变携带者对侧乳腺癌10年和20年的累积发病率分别为19.4%(sx 0.089)和50.3%(sx 0.155)。结论：中国汉族人群中BRCA1和BRCA2基因突变携带者具有很高的乳腺癌发病风险。因而对中国高风险人群进行BRCA1/2基因突变检测具有重要临床意义。     

Will Chinese ovarian cancer patients benefit from knowing the BRCA2 mutation status?

In Western countries,the mutation status of the BRCA1 and BRCA2 genes is commonly determined for genetic counseling among members of families with a history of breast or ovarian cancer,especially for w...