Cancer prevention: innovative strategies in the role of the European Cancer Prevention Organization.

Epidemiological studies demonstrate the key role of cancer prevention in reducing global cancer mortality. However, within Europe there are persisting important disparities in incidence and cancer-related mortality. The future strategy of cancer prevention will aim at reducing these disparities through abolition of tobacco educational campaigns to a correct diet and lifestyle through primary prevention, increasing screening (secondary prevention). We also consider focusing on genetics and precision oncology to identify high-risk individuals, and on tertiary prevention to reduce second cancer risk. The application of these approaches could reduce cancer mortality by 35% and increase cancer survival to 70% in 2070. Tobacco control and abolition remain key measures across Europe.

Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers.

BACKGROUND: Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. METHODS: We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. RESULTS: We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/ß-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. CONCLUSION: Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.

Prolonged recombinant pregnancy hormone use in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: An early first full-time pregnancy substantially reduces the risk of developing breast cancer later in life. Extensive studies indicate that this protective effect is mediated by the pregnancy hormone human chorionic gonadotrophin (hCG). METHODS: In this proof-of-concept study 33 women with a BRCA mutation received recombinant-hCG (r-hCG). A 4-mm breast biopsy was obtained before (T1) and after 12 weeks of r-hCG injections (T2), as well as 6 months later (T3). The tissue was examined using RNA-sequencing methodology to determine if the 'high-risk' transcriptomic signature was converted to a 'low-risk' signature as in an early first full-time pregnancy. A stringent clinical safety monitoring was performed. RESULTS: The r-hCG administration was well tolerated in all participants. No clinically relevant changes were observed. In 25 women, the RNA quality was good for RNA sequencing in all three breast tissue biopsies. In response to the r-hCG, we observed 1907 differentially expressed genes (DEGs) (1032 up, 875 down) at T2 vs. T1 and 1065 DEGs (897 up, 168 down) at T3 vs. T1 in the group of women (n = 11) not using any hormonal contraceptives during the study. There was no response at T2 vs. T1 and a small number of DEGs, 260 (214 up, 46 down) at T3 vs. T1 in the group of 14 women using contraceptives. CONCLUSIONS: In summary, r-hCG has a remarkable effect on the gene expression profile of breast tissues from BRCA1/2 carriers who did not use any contraception. This opens an opportunity for a novel preventive strategy to reduce the incidence of breast cancer.

Preventive, predictive, and personalized medicine for effective and affordable cancer care.

Preventive, predictive, and personalized medicine (PPPM) has created a wealth of new opportunities but added also new complexities and challenges. The European Cancer Prevention Organization already embraced unanimously molecular biology for primary and secondary prevention. The rapidly exploding genomic language and complexity of methods face oncologists with exponentially growing knowledge they need to assess and apply. Tissue specimen quality becomes one major concern. Some new innovative medicines cost beyond any reasonable threshold of financial support from patients, health care providers, and governments and risk sustainability for the health care system. In this review, we evaluate the path for genomic guidance to become the standard for diagnostics in cancer care and formulate potential solutions to simplify its implementation. Basically, introduction of molecular biology to guide therapeutic decisions can be facilitated through supporting the oncologist, the pathologist, the molecular laboratory, and the interventionist. Oncologists need to know the exact indication, utility, and limitations of each genomic service. Minimal requirements on the label must be addressed by the service provider. The interventionist is there to bring the most optimal tissue sample to pathology where the tissue is expanded to a variety of appropriate liquid-based samples. The large body of results then should be translated into meaningful clinical guidance for the individual patient. Surveillance, with the appropriate application of health economic indicators, can make this system long lasting. For governments and health care providers, optimal cancer care must result in a cost-effective, resource-sustainable, and patient-focused outcome.

Cancer prevention in Europe: the Mediterranean diet as a protective choice.

In the coming years, European death rates because of cancer will further decline, but the overall number of cases will increase, mostly as a consequence of the ageing of the population. The target for cancer prevention in Europe will remain a healthy diet and control of obesity in addition to a decrease in smoking. A healthy diet model in European countries is the traditional Mediterranean diet, which is based on abundant and variable plant foods, high consumption of cereals, olive oil as the main (added) fat, low intake of (red) meat and moderate consumption of wine. The Mediterranean diet is associated with a reduced risk of cardiovascular disease and cancer. The biological mechanisms for cancer prevention associated with the Mediterranean diet have been related to the favourable effect of a balanced ratio of omega 6 and omega 3 essential fatty acids and high amounts of fibre, antioxidants and polyphenols found in fruit, vegetables, olive oil and wine. The Mediterranean diet also involves a 'Mediterranean way of drinking', that is, regular, moderate consumption of wine mainly with food. This pattern of drinking increases longevity, reduces the risk of cardiovascular disease and does not appreciably influence the overall risk of cancer. However, heavy alcohol drinking is associated with digestive, upper respiratory tract, liver and breast cancers; therefore, avoidance or restriction of alcohol consumption to two drinks/day in men and one drink/day in women is a global public health priority.

Alcohol and wine in relation to cancer and other diseases.

Heavy alcohol consumption is associated with increased overall mortality, cancer, liver, and cardiovascular diseases; but low doses of alcohol (up to one drink per day) are not associated with the risk of any cancer site with the exception of breast cancer and possibly of oral and pharyngeal cancers. Moreover, recent evidence indicates that moderate alcohol and specifically wine intake provides cardioprotection and neuroprotection and may increase longevity. Various experimental data hypothesize a potential cancer chemopreventive role of some grape extracts, and complete sequencing of the grapevine genome has revealed genes responsible for the synthesis of health-promoting compounds (resveratrol and other polyphenols), thus advocating the development of future potential nutraceutical strategies. This focuses on the pros and cons of moderate alcohol and wine consumption and opens a debate on this topic.

Efficacy and safety of direct and frontal macrobiopsies in breast cancer.

Recent innovations in tissue acquisition from the human breast have led to the development of unique direct frontal systems. We intend to evaluate efficacy and safety in a multicenter clinical study. Efficacy was considered optimal if the diagnosis by transcutaneous biopsy was identical to the surgical specimen in case of malignancy or in line with clinical follow-up when benign. One hundred and seventy-three women (aged 22-95 years) with a suspect lesion in the breast were eligible for transdermal biopsy. One hundred and seventeen biopsies were performed with the Spirotome and 56 with the Coramate under radiological or ultrasound guidance. Sample quality was evaluated by comparing the pathology results of the samples with definitive pathology at subsequent surgery or follow-up in case of benign lesions. An average of 1.66 biopsies per procedure were obtained. All patients had sufficient sample size (up to 5 mm diameter/20 mm length) to make a reliable diagnosis. The average length was 1.39 cm and the average diameter 3.72 mm. There were three false-negative diagnoses, leaving a correct diagnosis in 170 patients. None of the patients suffered from a serious complication, and the procedure was generally well tolerated. The new direct frontal transdermal tissue acquisition approach gives adequate diagnostic results through high-quality tissue samples. No major patient discomfort was noted.

Percutaneous tissue acquisition: a treatment for breast cancer? Vacuum-assisted biopsy devices are not indicated for extended tissue removal.

Quite a number of radiologists indicate that complete removal of an imaged lesion in the breast by transdermal tissue acquisition is beneficial for the patient. Although this claim is technologically feasible with the vacuum-assisted biopsy (VAB) devices and, by virtue of a similar technology of aspiration, liposuction, there is no scientific or clinical proof that the extended procedure is indeed valuable for the patient. The optimal treatment of malignant or premalignant lesions remains open surgery with the goal to obtain pathologically free margins whenever possible. Complete removal by imaging is quite different from complete pathological removal. Hence, VAB elimination of suspect or malignant lesions can be considered less optimal and even malpractice in many cases. In addition, there is no evidence that complete removal of benign lesions is good for the patient. When benign lesions can be considered precursors for malignancy, they should be surgically removed as for other premalignant lesions. Most benign lesions can be treated medically as they are usually dispersed in the breast and hormone dependent. The rest of benign breast lesions need removal only to relieve the patient of psychological stress or because of symptoms. Evidence indicates furthermore that increase in cancer risk is related to the number and extent of breast interventions in the past. VAB and other large core biopsy devices remain a useful tool in the diagnosis of breast cancer but not for treatment purposes.

Human chorionic gonadotropin (hCG) and prevention of breast cancer.

Animal and 'in vitro' experiences learned that human chorionic gonadotropin (hCG) is capable to protect from breast cancer. Receptors for hCG/luteinizing hormone (LH) are present on human female and male breast cancer cells. hCG decreases proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-kappa B, AP-1 activation and other genes. Doxorubicin toxicity is enhanced by conjugation with beta-hCG in MCF-7 cells. All these pieces of evidence suggest that hCG is active in human breast cancer. Direct proof however is missing. We performed a pilot study phase I trial for testing the inhibitory effects or recombinant hCG (rhCG) on primary breast cancer. Twenty-five postmenopausal women with newly diagnosed breast cancers of more than 1.5 cm were biopsied before randomization to receive either 500 microg rhCG (n=20) or placebo. After 2 weeks, surgery was done and tissues were analysed with regard to morphological, immunohistochemical and biochemical changes in tissues and plasma. rhCG reduces significantly the proliferative index and the expression of both the oestrogen receptor and progesterone receptor. rhCG does not modify the hormonal level of estradiol, progesterone, inhibin and follicle stimulating hormone (FSH) but increases significantly the level of LH. In a second pilot study, we tested the clinical efficacy through an open-label single centre study in 13 postmenopausal women with metastatic breast cancer. A 500 microg rhCG once every 2 days shows activity in postmenopausal metastatic breast cancer. The time to progression is relatively short. Response to previous hormonal treatment is indicative for rhCG activity. Given the data in primary and metastatic breast cancer rhCG further large scale investigation is highly warranted. rhCG can be an realistic option in (chemo-) prevention trials.

Effects of lifestyle on the onset of puberty as determinant for breast cancer.

Breast cancer is more than ever the leading cause of death in women. In this article, we investigate the influence of lifestyle factors, and in particular nutrition (i.e. soft drinks), on physical development, puberty, breast growth and menarche to understand the potential impact of these environmental and lifestyle factors on the induction of breast cancer susceptibility. A questionnaire was obtained from 1146 girls of 10 schools in Belgian Limburg, attending the second year of secondary school. Their mean age was about 13 years. The analyses of the data were performed with 'survival analysis', in particular with the 'Cox regression' model for menarche. This project was conducted in the school year of 1999-2000. In the univariate and multivariate analysis investigating the most important variables of the period from birth to the age of menarche, there was clear evidence that lifestyle factors, including nutrition, have an effect on breast development and menarche. The following variables were significantly related to breast development and menarche: body mass index, drinking high-carbohydrate drinks, i.e. soft drinks, height of the father and the mother, weight of the mother at the start of pregnancy, history of mononucleosis, origin and education of the parents and physical activity. Lifestyle factors, including nutrition (i.e. soft drinks), affect the age at puberty and menarche. The same factors are known to be related to breast cancer risk. Better control of these variables during puberty might reduce breast cancer risk later in life.

Microdissection and SAGE as a combined tool to reveal gene expression in ductal carcinoma in situ of the breast.

The interplay between cancer cells and the normal surrounding tissue is believed to influence the biological behavior of the tumor. However, the presence of multiple cell types within the prelevated tumor specimen may attenuate changes that occur specifically in the malignant cells within their microenvironment. To study gene expression of the malignant cells in situ, we used a new microdissection method to separate ductal carcinoma in situ (DCIS) cells from the surrounding stroma, immunological infiltrates, and endothelial cells. We applied an adapted microSAGE protocol, without total mRNA amplification, to study their gene expression profile. Three thousand two hundred one different transcripts were identified in a total of 29 534 observed tags. Of these unique tags, 88.3% matched known GenBank sequences and 11.7% represented unknown transcripts. As compared to a total DCIS SAGE library, microdissection combined with SAGE revealed additional genes expressed only in normal surrounding, probably stromal, cells and not or significantly less in DCIS tumor cells. This study demonstrates that microdissection can be combined with SAGE as a tool to study transcriptomes. This approach provides important new information on differential gene expression both in tumor cells and normal surrounding tissue. Several of the observed differences indeed disappear when the total tumor mass is analyzed.