Prognostic difficulties of men with breast cancer.

Most adequately powered studies confirm a worse prognosis for males versus matched females with breast cancer. There is in-stage migration for stage I cancers with a different ratio of tumor/normal breast tissue in males. Younger men have a better prognosis, largely the result of increased morbidity in the elderly, exacerbated by smoking, low socioeconomic differences, and ethnic disparity. BRCA2 carriers with MBC have a worse outcome than noncarriers as do men with amplification of EMSY. Men with tumors having a high cytosol level of plasminogen activator inhibitor 1 (PAI-1) may have more invasive cancers leading to earlier spread and hence a worse outcome. PREDICT+ is a useful prognostic model for MBC and multigene testing enables more specific systemic therapies to be used.

Surgical options for male breast cancer.

BACKGROUND: Male breast cancer (MBC) is a rare disease for which no randomised controlled trials (RCT) have been conducted to determine optimal surgical management. The available data have been reviewed to identify reasonable options and reveal areas in need of investigation. METHODS: All published series on the surgical management of MBC have been reviewed to determine approaches to treatment of the primary, the breast and the axilla together with the psychological sequelae of surgery. FINDINGS: Mastectomy is still the major surgical offer but a convincing case can be made for the use of neoadjuvant endocrine treatment in order to facilitate breast conserving surgery. Sentinel node biopsy has been successfully used for staging MBC although nomograms for prediction of nodal status are inadequately calibrated. There are psychological sequelae of mastectomy in males and as yet no evidence that the needs of those with MBC are being met. CONCLUSIONS: Collaborative studies are required so that men can participate in meaningful RCTs to provide an evidence-based rational foundation for the surgery of MBC.

Progression of breast cancer following locoregional ipsilateral recurrence: importance of interval time.

BACKGROUND: Studies comparing prognosis of breast cancer (BC) patients with and without locoregional recurrence (LR) present conflicting results. We aimed to improve our understanding of the impact of LR on prognosis by examining a large cohort of patients treated at Guy's and St Thomas' NHS Foundation Trust. METHODS: Risk factors associated with BC-specific death were investigated using Cox proportional hazards regression in 5199 women diagnosed between 1975 and 2007. Breast cancer-specific death following LR was assessed with Poisson regression. RESULTS: Overall, 552 women (11%) developed LR, with a median follow-up time of 4.28 years. Known factors associated with BC-specific death (tumour stage, grade, and nodal status) were of significance in our data. Women with a shorter disease-free interval had a worse prognosis. For instance, the HR for BC-specific death among women undergoing mastectomy with an LR 0.5-1 year after diagnosis of their primary tumour was 6.67 (95% CI: 3.71-11.99), when compared with women who did not experience LR. CONCLUSIONS: It often remains difficult to distinguish between a genuine LR and a new primary. The HRs for risk of BC-specific death following a second lesion suggest that they may act as a marker of systemic disease, large tumour burden, or depleted host defence. The clinically highly relevant impairment in prognosis calls for further research into the underlying mechanisms. We showed that for at least 15 years of follow-up, the prognosis in women following the occurrence of an LR may benefit from careful diagnostic and therapeutic management.

Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial.

BACKGROUND: The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. METHODS: The EORTC 10801 trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. FINDINGS: After a median follow-up of 22·1 years (IQR 18·5-23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 [55%] in the MRM group and 274 [61%] in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92-1·38; p=0·23) or for time to death (1·11, 0·94-1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8-47·5) in the MRM group and 46·9% (42·2-51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3-49·5) in the MRM group and 39·1% (34·4-43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: <50 years 1·09 [95% CI 0·79-1·51] vs ≥50 years 1·16 [0·90-1·50]; overall survival <50 years 1·17 [0·86-1·59] vs ≥50 years 1·10 [0·89-1·37]). INTERPRETATION: BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. FUNDING: European Organisation for Research and Treatment of Cancer (EORTC).

Risk factors for male breast cancer.

Male breast cancer (MBC) presents problems with identification of high-risk groups. Risk factors include hepatic dysfunction, high ambient working temperature, exposure to exhaust fumes and obesity, but none identify a group with a high absolute number of MBC cases. The two significant cohorts are BRCA2 mutation carriers and individuals with Klinefelter's syndrome (KS), responsible for up to 15% of cases. Since >90% of male tumours are ER+ve, endocrine intervention is logical with the likely agent being tamoxifen. In terms of an acceptable endocrine agent, compliance studies. Compliance studies indicate that men do not tolerate tamoxifen well because of side-effects. Although certain groups with an increased risk of MBC can be identified, the absolute number of cases is small so, at present, a meaningful prevention study is not an option.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

BACKGROUND: Breast Health International and the Kimmel Cancer Center of Thomas Jefferson University cosponsored a consensus conference that included an international group of experts. METHODS: Since the adoption of adjuvant chemotherapy for stage I, lymph node-negative breast cancers in 1988, investigators have tried to "fine-tune" the treatment criteria. At this consensus conference, the group debated recommendations for adjuvant hormone and cytotoxic chemotherapy in stage I breast cancers. RESULTS: Discussions during the conference addressed issues of adjuvant therapy for stage I breast cancer and the influence of multigene analyses and molecular phenotyping. The panelists discussed various demographic, morphologic, biologic, and genetic factors expressed by individual tumors and their influence on treatment decisions. CONCLUSIONS: The panel tried to create guidelines for the consideration of adjuvant treatment of these patients, including both hormone and cytotoxic regimens. They also encouraged further research into the molecular analysis of breast cancers and the introduction of clinical trials based on current data, although they concluded that it is too early to add any of those analyses into the decision-making algorithms of recommendations for the treatment of stage I breast cancer.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients.

Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial.

BACKGROUND: Initial results of the UK/ANZ DCIS (UK, Australia, and New Zealand ductal carcinoma in situ) trial suggested that radiotherapy reduced new breast events of ipsilateral invasive and ductal carcinoma in situ (DCIS) compared with no radiotherapy, but no significant effects were noted with tamoxifen. Here, we report long-term results of this trial. METHODS: Women with completely locally excised DCIS were recruited into a randomised 2×2 factorial trial of radiotherapy, tamoxifen, or both. Randomisation was independently done for each of the two treatments (radiotherapy and tamoxifen), stratified by screening assessment centre, and blocked in groups of four. The recommended dose for radiation was 50 Gy in 25 fractions over 5 weeks (2 Gy per day on weekdays), and tamoxifen was prescribed at a dose of 20 mg daily for 5 years. Elective decision to withhold or provide one of the treatments was permitted. The endpoints of primary interest were invasive ipsilateral new breast events for the radiotherapy comparison and any new breast event, including contralateral disease and DCIS, for tamoxifen. Analysis of each of the two treatment comparisons was restricted to patients who were randomly assigned to that treatment. Analyses were by intention to treat. All trial drugs have been completed and this study is in long-term follow-up. This study is registered, number ISRCTN99513870. FINDINGS: Between May, 1990, and August, 1998, 1701 women were randomly assigned to radiotherapy and tamoxifen, radiotherapy alone, tamoxifen alone, or to no adjuvant treatment. Seven patients had protocol violations and thus 1694 patients were available for analysis. After a median follow-up of 12·7 years (IQR 10·9-14·7), 376 (163 invasive [122 ipsilateral vs 39 contralateral], 197 DCIS [174 ipsilateral vs 17 contralateral], and 16 of unknown invasiveness or laterality) breast cancers were diagnosed. Radiotherapy reduced the incidence of all new breast events (hazard ratio [HR] 0·41, 95% CI 0·30-0·56; p<0·0001), reducing the incidence of ipsilateral invasive disease (0·32, 0·19-0·56; p<0·0001) as well as ipsilateral DCIS (0·38, 0·22-0·63; p<0·0001), but having no effect on contralateral breast cancer (0·84, 0·45-1·58; p=0·6). Tamoxifen reduced the incidence of all new breast events (HR 0·71, 95% CI 0·58-0·88; p=0·002), reducing recurrent ipsilateral DCIS (0·70, 0·51-0·86; p=0·03) and contralateral tumours (0·44, 0·25-0·77; p=0·005), but having no effect on ipsilateral invasive disease (0·95, 0·66-1·38; p=0·8). No data on adverse events except cause of death were collected for this trial. INTERPRETATION: This updated analysis confirms the long-term beneficial effect of radiotherapy and reports a benefit for tamoxifen in reducing local and contralateral new breast events for women with DCIS treated by complete local excision. FUNDING: Cancer Research UK and the Australian National Health and Medical Research Council.

Prognosis of metachronous contralateral breast cancer: importance of stage, age and interval time between the two diagnoses.

Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy's and St. Thomas' Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5-4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation.

Prognostic Value of ER and PgR Expression and the Impact of Multi-clonal Expression for Recurrence in Ductal Carcinoma in situ: Results from the UK/ANZ DCIS Trial.

PURPOSE: The prognostic value of estrogen receptor (ER)/progesterone receptor (PgR) expression in ductal carcinoma in situ (DCIS) is unclear. We observed multi-clonality when evaluating ER/PgR expression in the UK/ANZ DCIS trial, therefore, we investigated the prognostic role of both uni-clonal and multi-clonal ER/PgR expression in DCIS. EXPERIMENTAL DESIGN: Formalin-fixed paraffin embedded tissues were collected from UK/ANZ DCIS trial participants (n = 755), and ER/PgR expression was evaluated by IHC in 181 cases (with recurrence) matched to 362 controls by treatment arm and age. Assays were scored by the Allred method and by a newly devised clonal method-analyses categorizing multi-clonal DCIS as ER/PgR-positive as per current practice (Standard) and as ER/PgR-negative (clonal) were performed. RESULTS: ER expression was multi-clonal in 11% (39/356) of ER-positive (70.6%, 356/504) patients. Ipsilateral breast event (IBE) risk was similarly higher in ER-multi-clonal and ER-negative DCIS as compared with DCIS with uni-clonal ER expression. ER-negative DCIS (clonal) had a higher risk of in situ IBE [OR 4.99; 95% confidence interval (CI), 2.66-9.36; P < 0.0001], but the risk of invasive IBE was not significantly higher (OR 1.72; 95% CI, 0.84-3.53; P = 0.14), P heterogeneity = 0.03. ER was an independent predictor in multivariate analyses (OR 2.66; 95% CI, 1.53-4.61). PgR status did not add to the prognostic information provided by ER. CONCLUSIONS: ER expression is a strong predictor of ipsilateral recurrence risk in DCIS. ER-positive DCIS with distinct ER-negative clones has a recurrence risk similar to ER-negative DCIS. ER should be routinely assessed in DCIS, and ER scoring should take clonality of expression into account.

Prognostic and Predictive Value of HER2 Expression in Ductal Carcinoma In Situ: Results from the UK/ANZ DCIS Randomized Trial.

PURPOSE: HER2 is overexpressed more frequently in ductal carcinoma in situ (DCIS) than in invasive breast cancer but its prognostic significance and predictive role for radiotherapy has not been clearly established. We investigated the prognostic and predictive value of HER2 overexpression in DCIS. EXPERIMENTAL DESIGN: HER2 expression was evaluated by IHC using the HercepTest™ in samples from UK/ANZ DCIS trial participants (n = 755) with IHC 3+ expression categorized as HER2 positive for primary analyses. Sensitivity analyses included HER2 categorization as negative (IHC 0,1+), equivocal (IHC 2+), and positive (IHC 3+) and analyses restricted to a nested case-control component where 181 cases (with recurrence) were matched to 362 controls by treatment arm and age. RESULTS: Two-hundred and forty-five (34.4%) of evaluable 713 samples [181 ipsilateral breast events (IBE)] were HER2 positive. HER2 overexpression was associated with significantly increased risk of IBE [HR = 2.29; 95% confidence interval (95% CI), 1.64-3.14; P < 0.0001] and in situ IBE (DCIS-IBE; HR = 2.90; 95% CI, 1.91-4.40; P < 0.0001), but not of invasive IBE (I-IBE; HR = 1.40; 95% CI, 0.81-2.42; P = 0.23; Pheterogeneity = 0.04). Inclusion of HER2 significantly improved [Δχ2 (1d.f.) 12.25; P = 0.0005] a prognostic model of clinicopathological and treatment variables, HER2 being an independent predictor of IBE (multivariate HR = 1.91; 95% CI, 1.33-2.76; P = 0.0004). Radiotherapy benefit in preventing DCIS-IBE was significantly greater (Pheterogeneity = 0.04) in HER2-positive DCIS (HR = 0.16; 95% CI, 0.07-0.41) compared with HER2-negative DCIS (HR = 0.58; 95% CI, 0.28-1.19). CONCLUSIONS: HER2 overexpression is associated with significantly increased risk of in situ recurrence and is also predictive of radiotherapy benefit, with greater reductions in in situ but not invasive recurrences in HER2-positive DCIS.

Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy.

An important class of genetic variants that affect disease susceptibility may lie within regulatory elements that influence gene expression. Regulatory sequences are difficult to identify and may be distant from the genes they regulate, but many lie within evolutionarily conserved regions (ECRs). We used comparative genomics to identify 12 ECRs up to 75 kb 5' to and within introns of IGF1. These were screened by high-resolution melting curve analysis, and 18 single-nucleotide polymorphisms (SNPs) were identified, including five novel variants. We analysed two large population-based series of healthy women to test the nine SNPs with minor allele frequency (MAF) >1% within ECRs. Three of the nine SNPs within ECRs (rs35455143, rs35765817 and rs3839984) were significantly associated with circulating IGF1 levels in a multivariate analysis (P 70 kb 5' of IGF1. Two (rs35455143 and rs35765817) are in strong LD with each other and appear to have opposite effects on circulating IGF1. Our results on a subset of other SNPs in or near IGF1 were consistent with previously reported associations with IGF1 levels, although only one (rs35767: P = 0.05) was statistically significant. We believe that this is the first systematic study of an association between a phenotype and SNPs within ECRs extending over a large region adjacent to a gene. Targeting ECRs appears to be a useful strategy for identifying a subset of potentially functional non-coding regulatory SNPs.

Meat, poultry and fish and risk of colorectal cancer: pooled analysis of data from the UK dietary cohort consortium.

OBJECTIVE: Some but not all epidemiological studies have reported that high intakes of red and processed meat are associated with an increased risk of colorectal cancer. In the UK Dietary Cohort Consortium, we examined associations of meat, poultry and fish intakes with colorectal cancer risk using standardised individual dietary data pooled from seven UK prospective studies. METHODS: Four- to seven-day food diaries were analysed, disaggregating the weights of meat, poultry and fish from composite foods to investigate dose-response relationships. We identified 579 cases of colorectal cancer and matched with 1,996 controls on age, sex and recruitment date. Conditional logistic regression models were used to estimate odds ratios for colorectal cancer associated with meat, poultry and fish intakes, adjusting for relevant covariables. RESULTS: Disaggregated intakes were moderately low, e.g. mean red meat intakes were 38.2 g/day among male and 28.7 g/day among female controls. There was little evidence of association between the food groups examined and risk for colorectal cancer: Odds ratios (95% confidence intervals) for a 50 g/day increase were 1.01 (0.84-1.22) for red meat, 0.88 (0.68-1.15) for processed meat, 0.97 (0.84-1.12) for red and processed meat combined, 0.80 (0.65-1.00) for poultry, 0.92 (0.70-1.21) for white fish and 0.89 (0.70-1.13) for fatty fish. CONCLUSIONS: This study using pooled data from prospective food diaries, among cohorts with low to moderate meat intakes, shows little evidence of association between consumption of red and processed meat and colorectal cancer risk.

Long-term results of breast conservation in Chinese women with breast cancer.

Between July 1989 and December 2002, 172 women with Stage I/II breast cancer were treated by breast conservation therapy (BCT). All underwent quadrantectomy and axillary node clearance. Minimum follow-up was 5 years and 79 (52%) were followed for >10 years. At 5 years, local relapse-free and overall survival rates were 98.3% and 98.3%. The 10-year rates were 95% and 94%, respectively. The 10-year local recurrence rate was higher in patients with involved margins (33.3% versus 2.7%, p = 0.0272). Furthermore 10-year death rates in margin positive patients were higher (18.2% versus 2.5%, p = 0.0486). Excellent or good cosmetic results were achieved in 54%. BCT is a reasonable option for early stage breast cancer in Chinese women but margin status is the most important determinant of local recurrence. Negative margins are required for optimal local control and minimization of distant metastasis.

Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007.

A consensus conference including thirty experts was held in April, 2007, to discuss risk factors for breast cancer and their management. Four categories of risk were outlined, from breast cancer "average" through "very high" risk, the latter including individuals with high penetrance BRCA1/2 gene mutations. Guidelines for management of patients in each of these categories were discussed, with the major portion of the conference being devoted to individuals with BRCA1/2 mutations. Prevalence of these mutations in the general populations was estimated to be 1 in 250-500 individuals, with an increased prevalence in Ashkenazic Jews and other founder groups. Risk reduction strategies for these individuals include surveillance, with or without chemoprevention drugs, or surgical procedures to remove the organs at risk, i.e., bilateral mastectomy and/or bilateral salpingo-oophorectomy. These risk reduction strategies were evaluated fully, and recommendations were made for the care of patients in each of the risk categories. These guidelines for patient care were approved by the entire group of experts.

Systemic lupus erythematosus and breast cancer.

There is evidence that certain connective tissue diseases such as scleroderma are associated with an increased risk of malignancy. Although it has been claimed that systemic lupus erythematosus (SLE) carries an increased risk of breast cancer, review of the available literature suggests that this is not the case, or, any increase is very small. Women with SLE do not need to be under close surveillance for breast cancer. In patients suffering from both SLE and breast cancer, radiotherapy has been regarded as relatively contraindicated because of fears concerning early and late complications. This view is not supported by the available literature and the majority of such cases can be treated by standard breast-conserving therapy, including breast irradiation.

Unmet needs of men with breast cancer.

Because of the rarity of male breast cancer (MBC) many men are unaware that the disease exists. This leads both to delay in presentation and severe distress after diagnosis concerning loss of masculinity and fear about the future. The informational and emotional support needs of men with breast cancer are often not met and many will have undiagnosed and untreated psychological morbidity. There is a pressing need for collaboration and the setting up national networks to improve both the treatment and quality of life of men with breast cancer.

Managing Male Mammary Maladies.

This review examines the symptoms, need for referral and management of the benign breast conditions which afflict males, together with the steps that are necessary to exclude or confirm male breast cancer. The most common complaint is gynaecomastia, either true or pseudo, and the majority of these cases need reassurance without over-investigation. Drugs that induce breast enlargement are described in order that, when possible, a medication switch can be made. Men receiving endocrine therapy for prostate cancer may develop painful gynaecomastia and this can be relieved with tamoxifen. All men with breast cancer need mammography as part of their work-up but this should not be used as a screening technique for symptomatic males. Because of lack of lobular development, both cysts and fibroadenomas are very rare in men; but those with nipple discharge need referral and investigation as some will have underlying malignancy.

The biology of male breast cancer.

Important differences have begun to emerge concerning the molecular profile of female and male breast cancer which may prove to be of therapeutic value. This review examined all the available data on the genomics of MBC. Most male cancers are ER+ve but without a corresponding increase in PR positivity and only a weaker association with estrogen-controlled markers such as PS2, HSP27 and Cathepsin-D. HER2 +ve cancers are rare in males and the role of androgen receptor is controversial. Although the Luminal A phenotype was the most frequent in both MBC and FBC, no Luminal B or HER2 phenotypes were found in males and the basal phenotype was very rare. Using hierarchical clustering in FBC, ERα clustered with PR, whereas in MBC, ERα associated with ERß and AR. Based on limited data it appears that Oncotype DX is effective in determining recurrence risk in selected MBC. In future, tailored therapies based on genomics will probably yield the most promising approach for both MBC and FBC.