Background Breast cancer is the most common cancer and the second most common cause of cancer-related death among North American and Western European women. Recent progress in understanding the genetic basis of breast cancer, along with rising incidence rates, have resulted in increased interest in prophylactic mastectomy as a method of preventing breast cancer, particularly in those with familial susceptibility. Objectives The primary objective was to determine whether prophylactic mastectomy reduces death from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast. The secondary objective was to examine the effect of prophylactic mastectomy on other endpoints including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. Search strategy Electronic searches were performed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cancerlit, and the Science Citation Index. Selection criteria Inclusion criteria were studies in English of any design type including randomized or nonrandomized controlled trials, cohort studies, case-control studies, and case series with at least ten participants. Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer, including subcutaneous mastectomy, total or simple mastectomy, modified radical mastectomy, and radical mastectomy. Data collection and analysis Information on patients, interventions, methods, and results were extracted by at least two independent reviewers. Methodological quality was assessed based on how well each study minimized potential selection bias, performance bias, detection bias, and attrition bias. Data for each study were summarized descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. Data were analyzed separately for bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM). Main results Twenty-three studies, including more than 4,000 patients, met inclusion criteria. No randomized or nonrandomized controlled trials were found. Most studies were either case series or cohort studies. All studies had methodological limitations, with the most common source of potential bias being systematic differences between the intervention and comparison groups that could potentially be associated with a particular outcome. Thirteen studies assessed the effectiveness of BPM. No study assessed all-cause mortality after BPM. All studies reporting on incidence of breast cancer and disease-specific mortality reported reductions after BPM. Nine studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have prophylactic mastectomy (PM) but more variable satisfaction with cosmetic results. Only one study assessed satisfaction with the psychological support provided by healthcare personnel during risk counseling and showed that more women were dissatisfied than satisfied with the support they received in the healthcare setting. Worry over breast cancer was significantly reduced after BPM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BPM. Three studies reported body image/feelings of femininity outcomes, and all reported that a substantial minority (about 20%) reported BPM had adverse effects on those domains. Six studies assessed contralateral prophylactic mastectomy. Studies consistently reported reductions in contralateral incidence of breast cancer but were inconsistent about improvements in disease-specific survival. Only one study attempted to control for multiple differences between intervention groups, and this study showed no overall survival advantage for CPM at 15 years. Two case series were exclusively focused on adverse events from prophylactic mastectomy with reconstruction, and both reported rates of unanticipated re-operations from 30% to 49%. Reviewers' conclusions While published observational studies demonstrated that BPM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. The studies need to be of sufficient duration and make better attempts to control for selection biases to arrive at better estimates of risk reduction. The state of the science is far from exact in predicting who will get or who will die from breast cancer. By one estimate, most of the women deemed high risk by family history (but not necessarily BRCA 1 or 2 mutation carriers) who underwent these procedures would not have died from breast cancer, even without prophylactic surgery. Therefore, women need to understand that this procedure should be considered only among those at very high risk of the disease. For women who had already been diagnosed with a primary tumor, the data were particularly lacking for indications for contralateral prophylactic mastectomy. While it appeared that contralateral mastectomy may reduce the incidence of cancer in the contralateral breast, there was insufficient evidence about whether, and for whom, CPM actually improved survival. Physical morbidity is not uncommon following PM, and many women underwent unanticipated re-operations (usually due to problems with reconstruction); however, these data need to be updated to reflect changes in surgical procedures and reconstruction. Regarding psychosocial outcomes, women generally reported satisfaction with their decisions to have PM but reported satisfaction less consistently for cosmetic outcomes, with diminished satisfaction often due to surgical complications. Therefore, physical morbidity and post-operative surgical complications were areas that should be considered when deciding about PM. With regard to emotional well-being, most women recovered well postoperatively, reporting reduced cancer worry and showing reduced psychological morbidity from their baseline measures; exceptions also have been noted. Of the psychosocial outcomes measured, body image and feelings of femininity were the most adversely affected.

Prophylactic mastectomy for the prevention of breast cancer

We present a review of current literature concerning the significance of serological markers in melanoma patients. Results for cytokines, cytokine receptors, cell adhesion molecules, S100 protein, melanoma inhibitory activity, tissue-specific reverse transcription-polymerase chain reaction, neurone-specific enolase, lipid-bound sialic acid and melanin metabolites such as 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid are discussed. For most of these substances, serum levels are more pronounced in the more advanced stages of disease. Therefore, these markers seem to have no place in the early detection of melanoma. On the other hand, sensitivity in the advanced stages of disease seems to be < 100%, compromising their use as a new staging procedure. Some markers show promising results as a possible prognostic factor in the early detection of disease progression or in the prediction of therapy outcome. If confirmed by further studies, this could direct future therapeutic strategies and could help to select patients who would benefit most from more aggressive (adjuvant) therapies. In addition, the study of some of these substances could add to the knowledge of tumour biology and immunology.

Serological markers for melanoma.

The agents responsible for the initiation of human mammary and prostatic cancers remain unidentified. Population migration studies on breast and prostate cancer risk have revealed that incidence rates in migrants from low-risk to high-risk ‘Westernized’ countries rise over time to match those of the host populations. The parallels suggest that the two diseases may share a common aetiology, with changes in diet, rather than in environment, being responsible for the migration-related increases in cancer incidence. Genotoxins, such as polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, are formed when foodstuffs are cooked at elevated temperatures and can be extracted with solvents: other genotoxins may only be released from cooked proteins when digestion occurs in the gastrointestinal tract. Human mammary and prostatic epithelial cells are known to be capable of metabolically activating members of different classes of chemical carcinogens to DNA-reactive species and, in rodents, five out of six mammary carcinogens can also induce prostatic neoplasms. Genotoxins have been detected in some 40% of breast lipid and milk samples donated by UK-resident women but the agents, currently thought to be of dietary origin, have not been characterized or identified as yet. Reduction mammoplasty and lactation both reduce breast cancer risk and the reduction is proportional either to the amount of tissue removed or to the total duration of lactation. As DNA damage has been detected in otherwise untreated mammary epithelial cells isolated both from breast tissue and from breast milk, we have proposed that reduction mammoplasty and lactation reduce risk through a common mechanism, i.e. the loss of pre-malignant cells. Further research, perhaps aimed particularly at the characterization of all the carcinogens formed when different dietary components are cooked in different ways, should succeed in identifying the agents that initiate breast and prostate cancer.

/pdf/the-initiation-of-breast-and-prostate-cancer-2810ao35ld.pdf

The initiation of breast and prostate cancer.

Background Urinary excretion of 5-S-cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression Melanomas produce not only 5-S-CD but also 5,6-dihydroxyindole-2-carboxylic acid (5,6DHI2C) as major intermediates in melanin formation 5,6DHI2C is then metabolized to the two O-methyl derivatives, 5H6MI2C and 6H5MI2C The aim of this study was to determine which marker in serum and urine most sensitively reflected the progression of melanoma

Methods Serum and 24-hour urine samples were collected and assayed serially by high-performance liquid chromatography every 1 to 4 months in 28 patients with primary or recurrent melanomas, for up to 48 months

Results Serum concentration and urinary excretion of 5-S-CD and 6H5MI2C in patients with melanoma without metastases were close to those obtained from normal subjects Metastases developed in 9 of the 28 patients In seven of these nine patients, serum or urinary 5-S-CD values were elevated before or at the time of clinical detection of visceral metastases However, serum 5-S-CD was elevated significantly earlier and reflected melanoma progression better than the physical examination and/or laboratory tests, such as scintigraphy and echography Serum 6H5MI2C values exceeded the normal range shortly before death in three patients, and urinary 6H5MI2C did not increase at any stage in most patients, therefore these metabolites did not reflect progression of disease

Conclusions Among the four markers, serum 5-S-CD appears to be the best biochemical marker for the detection of progression of melanotic melanoma, a value of more than 10 nmol/1 suggesting the presence of metastasis

Evaluation of melanin‐related metabolites as markers of melanoma progression

BACKGROUND

Women who undergo breast reduction operations have substantially lowered risks of breast cancer, and the reasons remain unclear. The current investigation attempted to assess whether the reduction in breast cancer risk was related directly to the amount of breast tissue removed.



METHODS

Medical record retrieval was attempted for 161 breast cancer patients in a Swedish cohort of 31,910 women who had had breast reduction surgery and for 483 women who had not developed breast cancer. Information on amount of breast tissue removed was abstracted along with other factors that influence breast cancer risk. Odds ratios of developing breast cancer were calculated based on amount of breast tissue removed.



RESULTS

The amount of tissue removed was a significant predictor of risk, as subjects in the highest quartile of tissue removal had a significantly lower risk than those in the lowest quartile. Considering the total amount of tissue removed (both breasts), subjects with ≥ 1600 versus < 800 grams removed had an odds ratio (OR) of 0.24 [95% confidence interval (CI) 0.1–0.5]. This relation persisted after adjustment for other breast cancer risk factors and was apparent within every subgroup examined.



CONCLUSIONS

The finding that breast cancer risk was reduced in proportion to the amount of tissue removed should be reassuring to women who are considering breast reduction procedures and to women who are electing to have bilateral total prophylactic mastectomies because of a strong genetic predisposition. Cancer 2001;91:478–83. © 2001 American Cancer Society.

Breast cancer risk in relation to amount of tissue removed during breast reduction operations in Sweden.

To determine whether plasma 5-S-cysteinyldopa levels are useful in following up patients at risk for melanoma, we measured plasma 5-S-cysteinyldopa in patients with dysplastic nevus syndrome and/or malignant melanoma and in control subjects. In patients with dysplastic nevus syndrome, plasma 5-S-cysteinyldopa levels did not differ from those in control subjects. Conversely, patients with malignant melanomas had significantly higher plasma 5-S-cysteinyldopa levels than did controls. Those with localized cutaneous malignant melanoma and no distant metastases (Stages I and II disease) had 5-S-cysteinyldopa levels twofold greater than those of control subjects, whereas the levels of those with regional lymph node involvement (Stage III disease) were fourfold greater than those of control subjects. Levels of those with extraregional metastases (Stage IV disease) were 7- to 450-fold higher than those of control subjects. Moreover, plasma 5-S-cysteinyldopa levels correlated with the spread of disease and were useful in distmguishing primary melanoma and Stages III and IV melanoma. We conclude that plasma 5-S-cysteinyldopa may be an important tool for identifying melanoma at an earlier, more curable stage and for following up patients at risk for the development of melanoma, for example, those with dysplastic nevus syndrome.

Plasma 5-S-cysteinyldopa differentiates patients with primary and metastatic melanoma from patients with dysplastic nevus syndrome and normal subjects†

Fifty-day-old female, albino Sprague-Dawley rats were induced with DMBA, a potent carcinogen that reliably causes multiple breast tumors. Prophylactic subcutaneous mastectomy was performed 2 weeks after injection. Control animals had no breast tissue removed and developed 5.14 tumors per animal, or 1.3 tumors per quadrant. Animals subjected to 50 percent (unilateral) mastectomy developed 5.4 tumors per animal, with 0.72 tumors per surgical quadrant. Animals that underwent 75 percent (three quadrant) mastectomy developed 4.33 tumors per animal, or 0.48 tumors per surgical quadrant. The incidence of tumors was significantly reduced in the surgical areas. However, the risk of any animal developing a breast neoplasm was not reduced in direct proportion to the percentage of breast tissue removed. We believe that this model may prove valuable in evaluating prophylactic subcutaneous mastectomy.

The effectiveness of prophylactic subcutaneous mastectomy in Sprague-Dawley rats induced with 7,12-dimethylbenzanthracene.

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Plasma 5-S-cysteinyldopa differentiates patients with primary and metastatic melanoma from patients with dysplastic nevus syndrome and normal subjects†

The effectiveness of prophylactic subcutaneous mastectomy in Sprague-Dawley rats induced with 7,12-dimethylbenzanthracene.