Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer.

BACKGROUND: Autoantibodies have been detected in sera before diagnosis of cancer leading to interest in their potential as screening/early detection biomarkers. As we have found autoantibodies to MUC1 glycopeptides to be elevated in early-stage breast cancer patients, in this study we analysed these autoantibodies in large population cohorts of sera taken before cancer diagnosis. METHODS: Serum samples from women who subsequently developed breast cancer, and aged-matched controls, were identified from UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and Guernsey serum banks to formed discovery and validation sets. These were screened on a microarray platform of 60mer MUC1 glycopeptides and recombinant MUC1 containing 16 tandem repeats. Additional case-control sets comprised of women who subsequently developed ovarian, pancreatic and lung cancer were also screened on the arrays. RESULTS: In the discovery (273 cases, 273 controls) and the two validation sets (UKCTOCS 426 cases, 426 controls; Guernsey 303 cases and 606 controls), no differences were found in autoantibody reactivity to MUC1 tandem repeat peptide or glycoforms between cases and controls. Furthermore, no differences were observed between ovarian, pancreatic and lung cancer cases and controls. CONCLUSION: This robust, validated study shows autoantibodies to MUC1 peptide or glycopeptides cannot be used for breast, ovarian, lung or pancreatic cancer screening. This has significant implications for research on the use of MUC1 in cancer detection.

Patterns of metastasis in women with metachronous contralateral breast cancer.

BACKGROUND: The understanding of metastatic patterns after metachronous contralateral breast cancer (CBC) may help determine the biological nature of CBC. METHODS: A cohort of 8478 women with breast cancer treated at Guy's and St Thomas' NHS Foundation Trust between 1975 and 2006 were studied. Organ-specific 5-year cumulative incidence and incidence rate ratios were assessed for women diagnosed with unilateral breast cancer (UBC), CBC within 5 years and CBC more than 5 years of the initial diagnosis. RESULTS: Women diagnosed with CBC within 5 years had a higher incidence of metastases in all organs compared with UBC. Women with a short interval time to CBC developed metastasis more rapidly and were more likely to develop visceral and distant cutaneous metastases compared with bone metastasis. CONCLUSION: These findings explain poor prognosis of women with early occurring CBC and suggest that some of these CBCs are indicators of aggressive and/or systemic disease.

Serum cotinine and prognosis in breast cancer.

Various studies have suggested that women who smoke have a worse prognosis if they develop breast cancer. Cotinine levels have been measured in sera from 511 patients with stage I and II breast cancer diagnosed between 1975 and 1980, all of whom had complete follow-up. Although the known prognostic factors, axillary nodal status, tumour size and grade were found to be significant, there was no relationship between serum cotinine and metastasis-free survival. A point estimate of serum cotinine was not found to be a determinant of survival in women with early breast cancer.

ZEN and the art of breast health maintenance.

Zearalenone (ZEN) is a non-steroidal mycoestrogen that widely contaminates agricultural products. ZEN and its derivatives share similar molecular mechanisms and activity with estrogens and interact with ERα and ERß leading to changes in the reproductive system in both animals and humans. The reduced form of ZEN, α-ZEA ralenol, has been used as an anabolic agent for animals and also proposed as hormonal replacement therapy in postmenopausal women. Furthermore, both zearelanol ZEN and derivatives have been patented as oral contraceptives. ZEN has been widely used in the United States since 1969 to improve fattening rates in cattle by increasing growth rate and feed conversion efficiency. Evidence of human harm from this practice is provided by observations of central precocious puberty. As a result, this practice has been banned by the European Union. As ZEN has been associated with breast enlargement in humans, it has been included in many bust-enhancing dietary supplements but epidemiological evidence is lacking with regard to breast cancer risk. Extensive work with human breast cancer cell lines has shown estrogenic stimulation in those possessing ER but a reduction in DMBA-induced breast cancers in rodents given ZEN. Protein disulfide isomerase provides a molecular biomarker of dietary exposure to ZEN and its derivatives allowing the detection and control of harmful food intake. The interaction of ZEN with anti-estrogens, anticancer agents and antioxidants requires further investigation.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Digital infrared thermal imaging (DITI) of breast lesions: sensitivity and specificity of detection of primary breast cancers.

AIM: To determine the sensitivity and specificity of digital infrared thermal imaging (DITI) in a series of women who underwent surgical excision or core biopsy of benign and malignant breast lesions presenting through the symptomatic clinic. MATERIALS AND METHODS: DITI was evaluated in 63 symptomatic patients attending a one-stop diagnostic breast clinic. RESULTS: Thermography had 90 true-negative, 16 false-positive, 15 false-negative and 5 true-positive results. The sensitivity was 25%, specificity 85%, positive predictive value 24%, and negative predictive value 86%. CONCLUSION: Despite being non-invasive and painless, because of the low sensitivity for breast cancer, DITI is not indicated for the primary evaluation of symptomatic patients nor should it be used on a routine basis as a screening test for breast cancer.

gamma-Glutamyl transferase and breast cancer risk.

BACKGROUND: It has been reported that there is an increased risk of cancer in individuals with elevated levels of serum gamma-glutamyl transferase (GGT). METHODS: In the Guernsey Breast Cancer Cohort Study, GGT was measured in sera from 1803 normal women. Among these women, 251 subsequently developed cancer, of whom 96 developed breast cancer. RESULTS: After adjustment for age at entry, height, weight, age at menarche and first birth with nulliparity, there was a highly significant relationship between elevated GGT and breast cancer risk. In the highest quartile, the hazard ratio (HR) was 2.17 (95% confidence interval (CI): 1.19, 3.93). When subdivided by menopausal status, there was a reduced non-significant effect in postmenopausal women, whereas for premenopausal women in the highest quartile, HR was 3.81 (95% CI: 1.37, 10.59). Premenopausal women with serum GGT levels above the normal range had a significantly elevated HR of 4.90 (95% CI: 1.86, 12.94). CONCLUSIONS: These results suggest that premenopausal women with high normal (above median) serum GGT or elevated levels (< or =40 IU l(-1)) are at increased risk of breast cancer and might benefit from close surveillance, possibly with breast magnetic resonance imaging scans. Serum GGT may mark previous exposure to carcinogens and lead to the identification of DNA adducts involved in mammary carcinogenesis.

A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR/ANZ DCIS trial.

BACKGROUND: There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR/ANZ DCIS trial have been histologically reviewed to determine the features of prognostic importance. METHOD: A total of 72% of 1694 cases entered into the UKCCCR/ANZ DCIS trial had full pathological review. A large number of histological features were assessed, blinded to outcome and compared regarding ability to predict ipsilateral recurrence, as either DCIS or progression to invasive carcinoma. RESULTS: Pathological features associated with ipsilateral recurrence in univariate analysis included high cytonuclear grade, larger lesion size, growth pattern, presence of necrosis or chronic inflammation, incompleteness (or uncertainty of completeness) of excision and smaller margin width. Receipt of post-operative radiotherapy was also a strong prognostic factor.We report a novel sub-division of the large group of high-grade lesions, which enables identification of a very poor prognosis sub-group; namely, DCIS that is of high cytonuclear grade, predominantly (>50%) solid architecture, bearing extensive comedo-type necrosis (>50% of ducts). In addition, we found little difference in ipsilateral recurrence rates between low- and intermediate-grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence. CONCLUSION: We present a novel pathological classification for DCIS with substantially better prognostic discrimination for ipsilateral recurrence than the classical categorisation based on cytonuclear grade alone.

Alcohol intake and risk of colorectal cancer: results from the UK Dietary Cohort Consortium.

BACKGROUND: Epidemiological studies have suggested that excessive alcohol intake increases colorectal cancer (CRC) risk. However, findings regarding tumour subsites and sex differences have been inconsistent. METHODS: We investigated the prospective associations between alcohol intake on overall and site- and sex-specific CRC risk. Analyses were conducted on 579 CRC cases and 1996 matched controls nested within the UK Dietary Cohort Consortium using standardised data obtained from food diaries as a main nutritional method and repeated using data from food frequency questionnaire (FFQ). RESULTS: Compared with individuals in the lightest category of drinkers (>0-<5 g per day), the multivariable odds ratios of CRC were 1.16 (95% confidence interval (95% CI): 0.88, 1.53) for non-drinkers, 0.91 (95% CI: 0.67, 1.24) for drinkers with 5-<15 g per day, 0.90 (95% CI: 0.65, 1.25) for drinkers with 15-<30 g per day, 1.02 (95% CI: 0.66, 1.58) for drinkers with 30-<45 g per day and 1.19 (95% CI: 0.75, 1.91) for drinkers with >or=45 g per day. No clear associations were observed between site-specific CRC risk and alcohol intake in either sex. Analyses using FFQ showed similar results. CONCLUSION: We found no significantly increased risk of CRC up to 30 g per day of alcohol intake within the UK Dietary Cohort Consortium.

What can be done about hot flushes after treatment for breast cancer?

Breast cancer survivors frequently experience severe hot flushes as a result of their treatment. This can adversely affect their quality of life, compliance with treatment and overall survival. To relieve vasomotor symptoms, a variety of drugs have been used including clonidine, gabapentin, selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors. Stellate ganglion block (SGB) has recently emerged as a new technique against hot flushes and preliminary studies report encouraging efficacy with minimal complications. Other approaches include various alternative treatments and, in a few cases, hormone replacement therapy (HRT). All randomized, controlled studies of drugs, hormone treatments and alternative therapies for vasomotor symptoms have been reviewed and efficacy and safety noted. Side-effects of current medical treatments frequently outweigh the benefits--leading many patients to discontinue the medications. Statistically significant differences between placebo and test agent may not translate into a meaningful subjective benefit. Desvenlafaxine looks promising as does SGB, despite its invasive nature. The favorable safety profile of SGB is confirmed through the long experience of SGB performed for other medical purposes. The majority of non-HRT treatments for hot flushes are little better than placebo but early results from randomized trials of desvenlafaxine and pilot studies of SGB suggest that it is worthwhile to test their efficacy specifically in breast cancer survivors.

Prognosis of synchronous bilateral breast cancer.

BACKGROUND: The prognosis of patients with synchronous bilateral breast cancer (SBBC) is usually based on the tumour with the worst pathological features. There is little evidence in the literature for this assumption, potentially impairing reasoned decisions on optimal adjuvant therapy. METHODS: This was a case-control study in which 68 women with SBBC were matched with 128 women with unilateral breast cancer. Both the GuysRisk prognostic model and the Nottingham Prognostic Index were used to determine the bilateral tumour with the poorer prognosis. Controls were matched for age, menopausal status, date of diagnosis, histological type and grade, and oestrogen receptor and axillary node status. RESULTS: Both prognostic models indicated the same side tumour with the worst prognosis. Kaplan-Meier survival curves for both disease-free and overall survival showed no significant difference in outcome between the two groups. CONCLUSION: Prognosis was determined by the tumour with the worst prognosis, with no additional worsening of outcome incurred from the second tumour.

Radiofrequency ablation in the treatment of primary breast cancer: no surgical redundancies yet.

BACKGROUND/INTRODUCTION: Radiofrequency energy has emerged as a new tool for the local destruction of cancer by inducing thermal tissue necrosis in the target region. Radiofrequency ablation (RFA) has recently been used to treat breast cancer primaries, potentially offering all the advantages of minimally invasive techniques. METHODS/EVIDENCE: Nine published studies addressing the role of RFA in the treatment of breast cancer have been identified and analysed, in six, first-line RFA was followed by surgical removal and there were 12 failures in 108 ablations. Three further studies involved RFA without subsequent excision and in 1/60 there was a local relapse after 4 months (follow-up range: 15-29 months). DISCUSSION: Existing RFA techniques may not be able to destroy the whole of the malignant lesion, because of local conditions allowing cancer cells to survive within the target area or because electrodes cannot be accurately directed to the tumour site with ultrasound. Additionally, distant in-breast cancers can be missed on pre/intraoperative imaging. Histological information is unavailable after tissue destruction so that the opportunity to reassess tumour grade based on more extensive sampling is lost, but this can be improved by more extensive sampling with vacuum-assisted core biopsy. CONCLUSIONS: Before RFA can be safely used in the treatment of breast cancer primaries, several criteria need to be met. These include development of RFA devices and techniques, standardisation of the treatment protocol, including imaging and selection of patients, and establishment of a feasible post-treatment follow-up strategy.

Gigantomastia: A problem of local recurrence.

Gigantomastia by definition means bilateral benign progressive breast enlargement to a degree that requires breast reduction surgery to remove more than 1800 g of tissue on each side. It is seen at puberty or during pregnancy. The etiology for this condition is still not clear, but surgery remains the mainstay of treatment. We present a unique case of Gigantomastia, which was neither related to puberty nor pregnancy and has undergone three operations so far for recurrence.

Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.

BACKGROUND: Breast-conserving therapy (BCT) has been shown to be as effective as mastectomy in the treatment of tumors 2 cm or smaller. However, evidence of its efficacy, over the long term, in patients with tumors larger than 2 cm is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried out a randomized, multicenter trial comparing BCT with modified radical mastectomy for patients with tumors up to 5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant metastasis, or time to locoregional recurrence. METHODS: Of 868 eligible breast cancer patients randomly assigned to the BCT arm or to the modified radical mastectomy arm, 80% had a tumor of 2.1-5 cm. BCT comprised lumpectomy with an attempted margin of 1 cm of healthy tissue and complete axillary clearance, followed by radiotherapy to the breast and a supplementary dose to the tumor bed. The median follow-up was 13.4 years. All P values are two-sided. RESULTS: At 10 years, there was no difference between the two groups in overall survival (66% for the mastectomy patients and 65% for the BCT patients; P =.11) or in their distant metastasis-free rates (66% for the mastectomy patients and 61% for the BCT patients; P =.24). The rate of locoregional recurrence (occurring before or at the same time as distant metastasis) at 10 years did show a statistically significant difference (12% of the mastectomy and 20% of the BCT patients; P =. 01). CONCLUSIONS: BCT and mastectomy demonstrate similar survival rates in a trial in which the great majority of the patients had stage II breast cancer.

Junctional intercellular communication pattern of cultured human breast cancer cells.

Junctional intercellular communication between several established human breast cancer cell lines and a variety of mammalian cells has been examined. All the cancer cell lines were found to be either noncommunicators or nonselective communicators. This contrasts with normal human mammary epithelium which shows selectivity in junctional communication. Loss of selectivity in junctional communication appears to be a general feature of cultured human breast cancer cells.