• SST/SSAs in cancer therapy
• colorectal cancer (CRC)
• mechanisms of antitumor activity
• neuroendocrine and non-endocrine tumors
• somatostatin (SST, SRIF)
• somatostatin analogues (SSAs)

• Breast cancer
• Cardiorespiratory fitness
• HIIT
• Inflammation
• MICT

• Humans
• Female
• Cardiorespiratory Fitness
• Breast Neoplasms
• Quality of Life
• Adipokines
• Cholesterol

• breast cancer survival
• diet
• evidence grading
• food
• systematic review

• Animals
• Dietary Supplements
• Diet
• Dietary Fats
• Neoplasms
• Vegetables

• 001 World Health Organization
• 25004 Cancer Research UK
• American Institute for Cancer Research
• Breast Cancer Research Foundation
• Wereld Kanker Onderzoek Fonds
• World Cancer Research Fund

• Body fatness
• breast cancer survival
• evidence grading
• systematic review
• weight change

• Humans
• Female
• Breast Neoplasms/epidemiology
• Body Mass Index
• Adipose Tissue
• Waist Circumference
• Waist-Hip Ratio

• 001 World Health Organization
• 25004 Cancer Research UK
• American Institute for Cancer Research
• Breast Cancer Research Foundation
• Wereld Kanker Onderzoek Fonds
• World Cancer Research Fund

• MYTHEN II detector
• octreotide
• synchrotron X-ray powder diffraction

• breast cancer
• estrogen receptor
• insulin receptor
• type I insulin-like growth factor receptor

• Breast Neoplasms/metabolism
• Female
• Humans
• Receptor, IGF Type 1/metabolism
• Receptors, Estrogen/metabolism
• Signal Transduction/physiology

• P30 CA077598 NCI NIH HHS

• BMI
• disease specific survival
• overall survival
• triple negative
• weight change

• Breast cancer
• Estrogen Receptor (ER)
• Insulin-like Growth Factor Binding Proteins (IGFBPs)
• Insulin-like Growth Factor-1 (IGF-1)
• Insulin-like Growth Factor-1 Receptor (IGF-1R)
• Targeted therapy

• BMI
• Obesity
• biology
• breast cancer
• inflammation
• insulin
• metabolic profile
• risk prognosis

• Clinical trials
• IGF-IR inhibitors
• Insulin-like growth factor (IGF)
• Monoclonal antibody
• Targeted therapeutics
• Tyrosine kinase inhibitors

• Breast cancer
• Diet
• Exercise
• Nutrition
• Obesity
• Physical activity
• Recurrence

• Biomarker standardization
• Centrally assessed breast cancer biomarkers
• RT-ER
• RT-HER2
• RT-PR

Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown.

The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland.

Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity.

Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer.

The online version of this article (doi:10.1186/s13058-016-0689-1) contains supplementary material, which is available to authorized users.

Acromegaly is a rare disease associated with an increased risk of developing cancer.

We report the case of a 72-year-old man who was diagnosed with acromegaly (IGF-1 770 ng/ml) and breast cancer. Four years before he suffered from a colon-rectal cancer. Pituitary surgery and octreotide-LAR treatment failed to control acromegaly. Normalization of IGF-1 (97 ng/ml) was obtained with pegvisomant therapy. Four years after breast cancer surgery, 2 pulmonary metastases were detected at chest CT. The patient was started on anastrozole, but, contrary to medical advice, he stopped pegvisomant treatment (IGF-I 453 ng/ml). Four months later, chest CT revealed an increase in size of the metastatic lesion of the left lung. The patient was shifted from anastrozole to tamoxifen and was restarted on pegvisomant, with normalization of serum IGF-1 levels (90 ng/ml). Four months later, a reduction in size of the metastatic lesion of the left lung was detected by CT. Subsequent CT scans throughout a 24-month follow-up showed a further reduction in size and then a stabilization of the metastasis.

This is the first report of a male patient with acromegaly and breast cancer. The clinical course of breast cancer was closely related to the metabolic control of acromegaly. The rapid progression of metastatic lesion was temporally related to stopping pegvisomant treatment and paralleled a rise in serum IGF-1 levels. Normalization of IGF-1 after re-starting pegvisomant impressively reduced the progression of metastatic breast lesions. Control of acromegaly is mandatory in acromegalic patients with cancer.

• Early breast cancer
• aromatase inhibitors
• endocrine therapy
• hormonal therapy
• hormone receptor–positive breast cancer
• ovarian ablation
• ovarian suppression
• tamoxifen

AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.

METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.

RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality.

CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

• Breast cancer
• Postmenopausal
• Hormone receptor positive
• Competing risks
• Tamoxifen
• Octreotide LAR

• P30 CA015083 NCI NIH HHS
• U10 CA180838 NCI NIH HHS

• adipokines
• inflammation
• insulin
• intervention

Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.

• Breast cancer
• Dietary pattern
• Nutrition
• Physical activity
• Vitamins

• Adult
• Age Factors
• Aged
• Breast Neoplasms/epidemiology
• Breast Neoplasms/physiopathology
• Breast Neoplasms/prevention & control
• Diet, Fat-Restricted
• Dietary Supplements
• Female
• Humans
• Incidence
• Life Style
• Middle Aged
• Motor Activity/physiology
• Nutritional Requirements
• Nutritional Status/physiology
• Obesity/prevention & control
• Primary Prevention/methods
• Prognosis
• Randomized Controlled Trials as Topic
• Risk Assessment
• Survival Analysis
• Weight Gain

• anti-inflammatory agents
• antioxidants
• chemotherapy
• long-term maintenance cancer therapy

• 25(OH)D
• breast neoplasms
• mortality
• recurrence
• vitamin D

• Animals
• Breast Neoplasms/etiology
• Breast Neoplasms/metabolism
• Female
• Humans
• Insulin/metabolism
• Insulin-Like Growth Factor I/metabolism
• Mice
• Obesity/complications
• Obesity/metabolism
• Risk Factors

The effectiveness of different breast cancer follow-up procedures to decrease breast cancer mortality are still an object of debate, even if intensive follow-up by imaging modalities is not recommended by international guidelines since 1997. We conducted a systematic review of surveillance procedures utilized, in the last ten years, in phase III randomized trials (RCTs) of adjuvant treatments in early stage breast cancer with disease free survival as primary endpoint of the study, in order to verify if a similar variance exists in the scientific world. Follow-up modalities were reported in 66 RCTs, and among them, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. The minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), with no relationship with the number of participating centers (P = 0.173), with pharmaceutical industry sponsorship (P = 0.80) and with trials enrolling > 1000 patients (P = 0.14). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008): Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences have been detected between North American and international RCTs. Stratifying the studies according to the date of beginning of patients enrollment, before or after 1998, in more recent RCTs the minimal approach is more frequently followed by international and North American RCTs (P = 0.01), by trials involving more than one country (P = 0.01) and with more than 50 participating centers (P = 0.02). It would be highly desirable that in the near future breast cancer follow-up procedures will be homogeneous in RCTs and everyday clinical settings.

• Breast cancer
• Endocrine resistance
• Insulin-like growth factor
• Oestradiol

• Animals
• Breast Neoplasms/etiology
• Breast Neoplasms/pathology
• Breast Neoplasms/prevention & control
• Cell Transformation, Neoplastic/pathology
• Estradiol/pharmacology
• Estrogens/pharmacology
• Female
• Humans
• Insulin-Like Growth Factor I/metabolism
• Receptors, Estrogen/metabolism
• Signal Transduction/drug effects

• 5-HIAA
• 5-hydroxyindoleacetic acid
• 70-kDa ribosomal protein S6 kinase
• ACTH
• AIP
• AKT8 virus oncogene cellular homolog
• Akt
• B-cell lymphoma 2
• BNCT
• Bax
• Bcl-2
• Bcl-2-associated X
• CCK
• DAG
• DOTA
• DR4
• DTPA
• Dopastatin
• GH
• GI
• GIP
• GLP-1
• GSK3β
• Grb
• Gsp
• Gsα subunit protein
• HGCT
• IGF-1
• IP3
• IRS-1
• JAK
• JNK
• Janus kinase
• LAR
• LDL
• MAPK
• Men1
• NET
• NHE1
• NOS
• Na(+)/H(+) exchanger
• Neuroendocrine tumor
• OGTT
• Octreotide
• PET
• PFS
• PI3K
• PIP2
• PKA/C
• PLA/C
• POMC
• PRL
• PTP
• Pasireotide
• Pituitary
• Proliferation
• RKIP
• Raf
• Raf kinase inhibitory protein
• Ras
• SH2
• SH2-containing phosphatase
• SHP
• SPECT
• SSTR
• STAT3/5b
• Signal transduction
• Somatostatin
• Somatostatin receptors
• Sos
• TNFR1
• TPE
• TSH
• TTP
• UFC
• VEGF
• Zac1
• adrenocorticotropic hormone
• aryl hydrocarbon receptor interacting protein
• boron neutron capture therapy
• c-Jun NH(2)-terminal kinase
• cAMP/cGMP
• cholecystokinin
• cyclic adenosine/guanosine monophosphate
• death receptor 4
• diacylglycerol
• diethylenetriaminepentaacetic acid
• gastrointestinal
• glucagon-like peptide 1
• glucose-dependent insulinotropic polypeptide
• glycogen synthase kinase 3β
• growth factor receptor bound protein
• growth hormone
• hyperglycemic clamp test
• inositol 1,4,5-trisphosphate
• insulin receptor substrate 1
• insulin-like growth factor 1
• long-acting release (or repeatable)
• low-density lipoprotein
• mTOR
• mammalian (or mechanistic) target of rapamycin
• mitogen-activated protein kinase
• multiple endocrine neoplasia 1
• neuroendocrine tumors
• nitric oxide synthase (endothelial/neuronal)
• oral glucose tolerance test
• p70/S6K
• phosphatidylinositol 3-kinase
• phosphatidylinositol 4,5-bisphosphate
• phospholipase A/C
• positron emission tomography
• pro-opiomelanocortin
• progression-free survival
• prolactin
• protein kinase A/C
• protein tyrosine phosphatase
• rapidly accelerated fibrosarcoma
• rat sarcoma
• rous sarcoma oncogene cellular homolog
• signal transducer and activator of transcription 3/5b
• single photon emission computed tomography
• somatostatin receptor
• son of sevenless
• src
• src homology 2
• tetraazacyclododecanetetraacetic acid
• thyroid-stimulating hormone
• time to tumor progression
• transient permeability enhancer
• tumor necrosis factor receptor 1
• urinary free cortisol
• vascular endothelial growth factor
• zinc finger protein that induces apoptosis and cell cycle arrest