Breast Cancer Chemoprevention by SOM230, an IGF-I Action Inhibitor
Breast Cancer Chemoprevention by SOM230, an IGF-I Action Inhibitor
This will be a proof of principle clinical trial to evaluate the use of pasireotide (SOM230)
 in women with ductal carcinoma in situ (DCIS) of the breast. Surgery and radiotherapy are
 used as treatment for DCIS and subsequent treatment with antiestrogens has been effective in
 reducing the occurrence of invasive breast cancer. Unfortunately, treatment with
 antiestrogens carries potential serious side effects and toxicities that are intolerable to
 some patients. Preliminary data suggest that inhibition of IGF-1 action in the breast will be
 at least as effective as tamoxifen. Pasireotide is a somatostatin analog that prevents
 mammary development by inhibiting IGF-1 action directly in the mammary gland and also
 indirectly without causing menopausal symptoms. This study is an expansion of work that we
 have previously done in women with atypical hyperplasia of the breast, which showed that
 treatment with pasireotide for 10 days caused a reduction in the cellularity of these
 precancerous lesions. In our present study, women with DCIS will be treated with pasireotide
 for 20 days prior to surgical excision. Endpoints will be as follows:

 1. To determine whether pasireotide will inhibit cell proliferation and angiogenesis (signs
 of tumor growth), and stimulate apoptosis (cell death) in surgically excised tissue in
 comparison to core biopsies from women with estrogen receptor (ER) positive DCIS. Both
 the core biopsy and surgical excision are standard of care procedures that women with
 DCIS have regardless of participation in this trial.

 2. To use dynamic contrast enhanced MRI to assess patients before and after treatment with
 pasireotide and evaluate for changes in tumor volume and other tumor related features

 3. In our previous study we found that many women experienced a slight elevation in blood
 sugar with 10 days of treatment with pasireotide. Other work has shown that this effect
 often resolves with greater duration of treatment. We are therefore expanding the
 duration of treatment in this study to 20 days to assess if the initial hyperglycemia
 seen with pasireotide improves as treatment duration progresses.
Ductal carcinoma in situ (DCIS) is a direct precursor of invasive breast cancer and is also a
 marker of an increased chance of developing invasive cancer in the ipsilateral and
 contralateral breast. Surgery and radiotherapy are used as treatment for DCIS and subsequent
 treatment with antiestrogens has been effective in reducing the occurrence of invasive breast
 cancer in DCIS patients. Unfortunately, treatment with antiestrogens carries potential side
 effects and toxicities. The investigators have data to suggest that inhibition of IGF-I
 action in the breast will be more effective than antiestrogens, raising hopes it might be
 effective enough to stand alone as a treatment. Pasireotide is a somatostatin analog that
 prevents mammary development by inhibiting IGF-I action directly in the mammary gland and
 also indirectly, without causing menopausal symptoms and signs. As both estrogen (E2) and
 progesterone (P) require IGF-I in order to act, part of the inhibitory effect of pasireotide
 is on prevention of estrogen action. The investigators have data that indicate that IGF-I
 also has direct actions on the breast that are independent of steroid hormones. One example
 is that IGF-I has a direct stimulatory effect on mammary development in the absence of E2.
 Additionally, IGF-I has effects on ER-negative tumor cell lines that can be reversed by IGF-I
 inhibition. If pasireotide inhibited both E2 related and E2 unrelated effects of IGF-I it
 would likely be more effective than antiestrogens. Preliminary data in rats show that
 pasireotide, at minimum, can entirely substitute for tamoxifen. To determine whether
 pasireotide had activities in women at high risk for breast cancer, similar to those observed
 in rats, the investigators were awarded a DOD Synergistic Idea grant. Those data are expected
 to be reported soon.

 The investigators plan to expand this work to determine in principle whether pasireotide has
 the potential to treat DCIS. The investigators plan on treating 24 women, with low grade (8),
 intermediate grade (8) and high grade (8) ER-positive DCIS tumors. The investigators will
 assess its effect on apoptosis, cell proliferation, angiogenesis, ER and PR and
 phosphorylation of IGF-IR and IRS-1 before and after 20 days of treatment with pasireotide in
 core biopsy vs. surgical excision specimens. These endpoints will be measured by specific
 immunohistochemistry. Simultaneously, the investigators will determine whether IGF-I
 inhibition will reduce angiogenesis in DCIS using dynamic contrast enhanced MRI (DCE-MRI) at
 3.0 Tesla, in addition to mammography. This MRI technique is able to detect early changes of
 neo-angiogenesis associated with invasive breast cancers and DCIS. Pasireotide should
 theoretically inhibit angiogenesis in these women, as it does in mice. The DCE-MRI may also
 show changes in tumor volume, morphologic and kinetic features. Imaging will serve as an
 additional measure to monitor response to treatment. Results will be correlated with
 pathology and immunohistochemical endpoints.

 In our previous work the investigators noted that there was an increase in blood glucose
 early after starting pasireotide, but the work of others has indicated that this side effect
 lasts only several weeks. The investigators found that suppressed levels of insulin (due to
 pasireotide effect on β cells) began to rise by day 10 of treatment. Therefore, extending the
 treatment period from 10 to 20 days with daily monitoring of patients will enable us to make
 certain that the early elevated glucose associated with pasireotide is only temporary.
 Another side effect is reduction in circulating levels of IGF-I. Theoretically, this could
 lead to body changes associated with growth hormone deficiency (GHD). Although, tamoxifen and
 raloxifene also lower serum IGF-I, and women taking it do not usually complain of symptoms of
 GHD, this is an issue that must be further investigated. However, if pasireotide is found to
 be effective in the treatment of DCIS, the benefit would likely outweigh the risk.
Inclusion Criteria:

 -  21 years of age and older

 -  Must sign informed consent, witnessed, and dated prior to entry

 -  The participant has breast biopsy consistent with Ductal Carcinoma in situ (DCIS)

 -  Performance Status: ECOG 0-1 unless mobility is limited from chronic physical handicap

 -  No clinical evidence of other malignancies (except Basal Cell carcinoma)

 -  Complete blood count, differential and platelet count must be WNL or verified by the
 study chair to be related to conditions not interfering with normal health status

 -  Adequate hepatic and renal function (these must be WNL or verified by study chair to
 be related to conditions not interfering with normal health status)

 -  Normal fasting glucose

 -  No history of diabetes

 -  Medically and Psychologically able to comply with all study requirements

 -  Accessible for Follow up

 Exclusion Criteria:

 -  Less than 21 years of age

 -  Known invasive breast cancer of any type

 -  Bilateral prophylactic mastectomy

 -  Prior malignancy of any type that occurred less than 5 years previously, except for
 basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix

 -  Existing non-malignant disease that would preclude the administration of pasireotide

 -  Pregnancy: All subjects will have a beta-hCG serum pregnancy test to rule out
 pregnancy, a history will also be taken to make certain that recent sexual exposure
 does not put them at risk for pregnancy. If so a second serum pregnancy test will be
 done. Volunteers will be asked to use barrier contraception during study.

 -  Tamoxifen or other preventive measures within 6 months

 -  Serious Psychiatric condition or addictive disorder

 -  Diabetes or elevated fasting blood sugar either by history or by HgbA1c greater than
 6.5% or fasting serum glucose greater than 100mg/dL on screening labs. If fasting
 serum glucose is greater than 100mg/dL on screening labs, this test will be repeated
 to confirm the results

 -  Inability to inject medication or test for finger stick glucose

 -  Gall bladder disease

 -  History of cholecystitis without cholecystectomy

 -  Electrolyte abnormalities (particularly hypokalemia or hypomagnesemia)

 -  Contraindication for MRI

 -  If tumor size is < 1cm on mammography and all calcifications are removed on core
 biopsy the patient will be excluded.

 QT related exclusion criteria

 -  QTcF at screening > 450 msec.

 -  History of syncope or family history of idiopathic sudden death.

 -  Sustained or clinically significant cardiac arrhythmias.

 -  Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac
 failure, clinically significant/symptomatic bradycardia, or high-grade AV block.

 -  Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by
 diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or
 cardiac failure

 -  Concomitant medication(s) known to increase the QT interval.

 Hepatic Related Exclusion Criteria

 -  Baseline Alanine transaminase (ALT) or Aspartate transaminase (AST) > 2x upper limit
 of normal (ULN) without known complications of metastatic liver disease or primary
 hepatic disease (e.g. Cushing's disease and Acromegaly studies).

 -  Baseline Total Bilirubin > 1.5x ULN