(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/169611 Al 14 November 2013 (14.11.2013) P O P C T

(51) International Patent Classification: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, A61K 39/395 (2006.01) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (21) International Application Number: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, PCT/US20 13/0396 12 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (22) International Filing Date: ZM, ZW. 6 May 2013 (06.05.2013) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/644,484 ' May 2012 (09.05.2012) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: MERCK SHARP & DOHME CORP. TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [US/US]; 126 East Lincoln Avenue, Rahway, New Jersey ML, MR, NE, SN, TD, TG). 07065-0907 (US). Declarations under Rule 4.17 : (72) Inventor; and — as to applicant's entitlement to apply for and be granted a (71) Applicant (for US only): SATHYANARAYANAN, Sri- patent (Rule 4.1 7(H)) ram [US/US]; 33 Avenue Louis Pasteur, Boston, Mas sachusetts 021 15-5727 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (74) Common Representative: MERCK SHARP & DOHME CORP.; 126 East Lincoln Avenue, Rahway, New Jersey Published: 07065-0907 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, — with sequence listing part of description (Rule 5.2(a)) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,

(54) Title: COMPOSITIONS AND METHODS FOR TREATING BREAST

FIG. 1

(57) Abstract: The instant invention provides methods of treating in a subject suffering there from comprising admin o istering a therapeutically effective amount of an mTor inhibitor, an anti-IGF-IR antibody and an aromatase inhibitor. In one embodi - ment of the methods of the invention, the mTOR inhibitor is rapamycin, a rapamycin analog selected from ridaforolimus, ever - olimus, or temsirohmus, or a combination thereof. In another embodiment of the methods of the invention, the anti-IGF-1 R anti o body is selected from , , , , , Roche RI507 and EM164. In a further embodiment, the aromatase inhibitor is selected from letrozole, exemestane, fulvestrant or anastrozole. COMPOSITIONS AND METHODS FOR TREATING BREAST CANCER

BACKGROUND OF THE INVENTION The phosphatidylinositol-3 -kinase (PI3K) signaling pathway is important for the growth and survival of cancer cells in many different types of human malignancy (see, Granville, C.A. et al, 2006, Clin. Cancer Res. 12:679-89). This pathway receives upstream input from ligand-receptor interactions, such as the epidermal receptor and -like , and signals through downstream effectors, such as the mammalian target of rapamycin (mTOR). Dysregulation of the PI3K axis is common in human cancer due to overactive growth factor receptor signaling, activating mutations of PI3K, loss of function of the PTEN tumor suppressor, and several other mechanisms that result in activation of mTOR kinase activity. Clinically, successful pharmacological inhibition of the PI3K axis has focused on the upstream growth factor receptors and the downstream effectors of PI3 kinase. The role of the PI3K signaling pathway has been well established in the cellular processes of breast cancer (see, e.g., Lopez-Knowles, E. et al, 2010, Int. J. Cancer 126:1 121-1 131). mTOR is a crucial downstream effector molecule that regulates the production of proteins critical for cell cycle progression and many other important cellular growth processes (see, e.g., Abraham, R.T. and Gibbons, J.J., 2007, Clin. Cancer Res. 13:3109-14. It receives signaling inputs from a number of important growth factor receptors that use the PI3K signaling axis, serving as an effector molecule of those signals by controlling the translation of a number of proteins that are critical for cell cycle progression, nutrient transport, tumor angiogenesis, and many other processes. mTOR can be activated in cancer cells by abnormal or inappropriate growth factor signaling, mutation or activation of signaling molecules such as PI3K or Akt, or the loss of the PTEN tumor suppressor molecule. There is now substantial clinical evidence showing that mTOR inhibitors can provide clinical benefit to patients with advanced malignancies (see, e.g., Polunovsky, V. A., and Peter J. Houghton, eds. mTOR Pathway and mTOR Inhibitors in Cancer Therapy, New York: Humana Press, 2010). Insulin-like growth factor receptor 1 (IGF-1R), a receptor of the insulin receptor family that sits upstream of mTOR in the PI3K pathway, is involved in cell proliferation and differentiation and plays an important role in the transformation and maintenance of malignant cells in many types of cancer. See, Baselga, R, et al., 2003, Int. J. Cancer 107:873-77. IGR-1R and its ligand IGF-2 are over-expressed in many types of advanced cancer, and ligand-stimulated receptor signaling promotes the proliferation of cancer cells in vitro. IGF-IR signaling is closely linked to the PI3K axis (see, e.g., Riedemann, J. and Macaulay, V.M., 2006, Endocrine-Related Cancer 13:S33-S43). IGF-IR inhibition has shown potent anti-cancer effects in preclinical studies, and a number of IGF-IR inhibitors are currently in clinical development (see, e.g., Weroha, S.J. and Haluska, P., 2009, J. Mammary Gland Biol. Neoplasia 13:471-483). Studies have demonstrated the IGFR pathway plays an important role in the signal transduction pathways involved in breast cancer (see, e.g., Hartog, H. et al, 2012, Anticancer Res. 32:1309-1318). The inhibition of mTOR leads to activation of a feedback loop that activates the Akt oncogene, as shown by increased levels of phosphorylated Akt in both tumor cells in vitro after rapamycin inhibition and tumor biopsies taken from patients treated with mTOR inhibitors (see, Sun, S-Y et al, 2005, Cancer Res. 65:7052-58; and Gardner, H et al, "Biomarker analysis of a phase II double-blind randomized trial of daily oral RADOOl (everolimus) plus letrozole or placebo plus letrozole as neoadjuvant therapy for patients with estrogen receptor positive breast cancer," Abstract 4006, San Antonio Breast Cancer Symposium, San Antonio, TX, December 13-16, 2007). This feedback loop can involve signaling through IGF-IR and the insulin receptor substrate, and is inhibited by IGF-IR inhibitors. Preclinical studies have shown that the combination of IGF-IR inhibitors and mTOR inhibitors leads to additive or synergistic anti- tumor activity in vitro, inhibiting both upstream and downstream molecular targets in the PI3K axis. Two groups independently reported results of combining rapamycin with anti-IGF-lR antibodies in xenograft models of human sarcomas (see, Kurmasheva ,R.T. et al., "Combination of CP-751871, a human against the IGF-1 receptor with rapamycin results in highly effective therapy for xenografts derived from childhood sarcomas," Abstract CI72, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, October 22-26, 2007, San Francisco, CA; and Darko, LA. et al., "Evaluation of combined insulin-like growth factor receptor type I (IGF-IR) and mTOR pathway blockade in sarcoma xenograft models," Abstract 4760, 98th AACR Annual Meeting, April 14-18, 2007, Los Angeles, CA). Additionally, the combination of an mTOR inhibitor, ridaforolimus, and an anti- IGF-1R antibody, dalotuzumab, in human lung cancer cell lines was more effective in blocking PI3K signaling than either agent alone (see, PCT International Patent Application serial no. PCT/US20 10/030074, published as WO 2010/120599 on October 21, 2010). RNA interference enhancer screens have also identified the combination of IGF- IR and mTOR inhibitors as one of high interest for the potential treatment of human . A short-hairpin (sh)RNA kinome library screen identified mTOR (also known as FRAPl) as a top hit to mediate the ability of an anti-IGF-lR antibody, dalotuzumab, to suppress proliferation in HT-29 cells. Conversely, a short-interfering (si)R A genomic screen using HT-1080 cells treated with an mTOR inhibitor, ridaforolimus, identified IGF-IR and several components of the IGF-IR signaling pathway, as the primary mediator of the A t feedback activation noted with ridaforolimus treatment. These results underscore the centrality of the IGFlR-mTOR relationship in tumor proliferation and feedback regulation of Akt. There is also accumulating evidence suggesting that the crosstalk between the PI3K pathway and the estrogen receptor (ER) pathway is a major determinant of endocrine sensitivity, (Perez-Tenorio et al, 2007, Clin. Cancer Res. 13:3577-3584; Stemke-Hale et al, 2008, Cancer Res. 68:6084-6091; Creighton et al, 2010, Breast Cancer Res. 12:R40). A Phase I clinical study has shown a preliminary signal of anti-tumor activity in patients treated with the mTOR inhibitor, ridaforolimus, and the IGF-IR inhibitor, dalotuzumab, in estrogen receptor positive patients. See Ebbinghaus, S. et al, "A phase II study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor-positive (ER+) breast cancer," Abstract TPS 110,

201 1ASCO Annual Meeting, June 3-7, 201 1, Chicago, IL; and Ebbinghaus, S., "Dual inhibition of mTOR and IGF1R pathways," Abstract CN02-02, AACR-NCI-EORTC International

Conference: Molecular Targets and Cancer Therapeutics, Nov. 12-16, 201 1, San Francisco, CA. In this Phase I study, objective responses were reported in patients with breast cancer, non-small cell lung cancer, ovarian cancer, and other solid tumors. Among women with breast cancer, the activity signal appeared to derive predominantly from patients with estrogen receptor (ER) positive and high proliferation (based on assessment of Ki67 from the primary tumor) luminal B- like tumors that were refractory to endocrine therapy. Among these patients, the objective response rate was 27% (3 of 11 patients), but other evidence of anti-tumor activity included declines in tumor markers (CA15.3), metabolic activity by FDG-PET scanning, and prolonged stable disease for greater than 6 months. Collectively, 6 of 11patients with ER+ high proliferation breast cancer had objective evidence of the activity of the combination based on one or more of these parameters. A Phase II study with the ridaforolimus-dalotuzumab combination is currently ongoing in patients with ER+ high proliferation breast cancer that has shown to be refractory to endocrine therapy. Pre-clinical studies also demonstrate that co-targeting of mTOR and ER can be effective in hormone refractory models of ER+ breast cancer. Acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both the ER and PI3K pathways (Miller, T.W. et al, 2010, J. Clin. Invest. 120:2406-2413). mTOR inhibition in combination with anti-estrogen agents can act in a synergistic manner to inhibit proliferation in

ER+ tumor cells and trigger apoptotic cell death in vitro (Sanchez, C.G. et al, 201 1, Breast Cancer Research 13:R21). This combination was also active in hormone refractory models of breast cancer. Baselga et al, (2012, N. Engl. J. Med. 366:520-529) describes results of a Phase III study comparing progression-free survival (PFS) of the non-steroidal aromatase inhibitor, exemestane, to the combination of exemestane and everolimus (an mTOR inhibitor). In this study of 150 post-menopausal women with ER+, HER2 negative breast cancer who had progressed after treatment with a non-steroidal aromatase inhibitor, the mTOR/aromatase inhibitor combination demonstrated an advantage. To identify additional treatment options for patients with breast cancer, a combination of therapies focusing on the crosstalk between the PI3K/AKT/mTOR pathway, the ER-pathway and the IGFR pathway are disclosed. International PCT application no. PCT/US20 10/030074 (published as WO 2010/120599), filed April 6, 2010, describes methods of treating cancer selected from the group consisting of non-small cell lung cancer, breast cancer, colorectal cancer, soft tissue or bone sarcomas and endometrial cancer with an mTOR inhibitor and an anti-IGF-lR antibody.

SUMMARY OF THE INVENTION The instant invention provides methods of treating breast cancer in a subject {e.g., a mammal such as a human) suffering there from comprising administering to said subject a therapeutically effective amount of an mTOR inhibitor, an anti-IGF-lR antibody, and an aromatase inhibitor. In one embodiment of the methods of the invention, the mTOR inhibitor is rapamycin, a rapamycin analog selected from ridaforolimus, everolimus, or temsirolimus, or a combination thereof. In another embodiment of the methods of the invention, the anti-IGF-lR antibody is selected from dalotuzumab, robatumumab, figitumumab, cixutumumab, ganitumab, Roche R1507 and EM164. In a further embodiment, the aromatase inhibitor is selected from letrozole, exemestane, fulvestrant or anastrozole.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1, adapted from Sotiriou et al, 2009, N. Engl. J. Med. 360:790, shows the classification of types of breast cancer by molecular and receptor analyses. FIGURE 2 shows that the triple combination of ridaforolimus, dalotuzumab and letrozole causes tumor regressions in the MCF7-Aro xenograft model. A) Tumor growth inhibition curves with the indicated therapies. Let: letrozole; Dalo: dalotuzumab; Rida: ridaforolimus; Reg: tumor regression. B) IGFIR, P-[Ser473] AKT, progesterone receptor (PR) and estrogen receptor (ERa) expression from MCF7-Aro tumors. Lanes - 1: control; 2 : letrozole; 3 : dalotuzumab; 4 : letrozole and dalotuzumab; 5: ridaforolimus; 6 : ridaforolimus and dalotuzumab.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods of treating patients suffering from breast cancer with a triplet combination of an mTOR inhibitor (or a pharmaceutically acceptable salt thereof), an anti-IGF-1 receptor ("anti-IGF-lR") antibody, and an aromatase inhibitor. In one embodiment, the invention is useful for the treatment of patients diagnosed with estrogen receptor positive ("ER+") breast cancer, including but not limited to ER+ breast cancer characterized as having an increased proliferation rate (i.e., Luminal B-type breast cancer). The mTOR inhibitor used in the treatment methods of the invention may be rapamycin, a rapamycin analog selected from ridaforolimus, everolimus or temsirolimus, or a combination thereof. In one embodiment, the mTOR inhibitor is a rapamycin analog selected from ridaforolimus, everolimus or temsirolimus. In another embodiment, the mTOR inhibitor is ridaforolimus. The anti-IGF-1R antibody used in the treatment methods of the invention may be selected from dalotuzumab, robatumumab, figitumumab, cixutumumab, ganitumab, Roche R1507 and EM164. In one embodiment, the anti-IGF-lR antibody is dalotuzumab. The aromatase inhibitor used in the treatment methods of the invention may be a steroidal aromatase inhibitor or a non-steroidal aromatase inhibitor. In one embodiment of the methods of the present invention, the aromatase inhibitor is selected from letrozole, exemestane, fulvestrant or anastrozole. In another embodiment, the aromatase inhibitor is a steroidal inhibitor. In a further embodiment, the aromatase inhibitor is exemestane. Accordingly, the instant invention relates to methods of treating breast cancer in a subject suffering there from (e.g., a human patient diagnosed with breast cancer) comprising administering to said subject/patient a therapeutically effective amount of an mTOR inhibitor, an anti-IGF-1R antibody, and an aromatase inhibitor, wherein the mTOR inhibitor is rapamycin, a rapamycin analog selected from ridaforolimus, everolimus or temsirolimus, or a combination thereof, the anti-IGF-1R antibody is selected from dalotuzumab, robatumumab, figitumumab, cixutumumab, ganitumab, Roche R1507 and EM164, and the aromatase inhibitor is selected from letrozole, exemestane, fulvestrant or anastrozole. In another embodiment, the subject/patient is treated by administering a therapeutically effective amount of a rapamycin analog selected from ridaforolimus, everolimus or temsirolimus, an anti-IGF-1R antibody that is dalotuzumab, and an aromatase inhibitor that is exemestane or anastrozole. In a further embodiment, the subject/patient is treated by administering a therapeutically effective amount of ridaforolimus, dalotuzumab and exemestane. In one embodiment, the treatment methods of the present invention are used in post-menopausal women who have progressed after prior treatment with an aromatase inhibitor. In another embodiment, the prior treatment was with a non steroidal aromatase inhibitor. In a further embodiment, the subject/patient as estrogen receptor positive breast cancer. Breast cancer is a heterogeneous group of cancer types defined by the presence of the estrogen, progesterone and HER2/neu receptors, histological grade, and expression of families of proliferation genes. "Estrogen receptor positive breast cancer" refers to breast cancers that are in the positive or intermediate range for the estrogen receptor protein. This suggests that the cancer cells, like normal breast cells, may receive signals from estrogen that could promote their growth. Receptor status generally correlates with patterns of expression of proliferation genes. Indeed, molecular and receptor analyses have led to the definition of several types of breast cancer, each having different clinical courses and responses to targeted and cytotoxic therapies (see FIGURE 1). Current therapy decision-making is increasingly directed by the molecular classification of breast cancer. Gene expression profiling of breast cancer has identified at least four different subtypes of breast cancer associated with varying degrees of responsiveness to systemic therapy and different long-term outcomes: basal- like, HER2 -positive, Luminal A, and Luminal B (see

FIGURE 1). The Luminal B subtype is characterized by ER expression, lack of HER2 over- expression, and evidence of increased cellular proliferation as identified, for example, by Ki67 labeling index (Cheang, M.C.U. et al, 2009, J. Natl. Cancer Inst. 101:736-750; Castaneda, C.A. et al., 201 1, J. Clin. Oncol. 29:201 1 (supplement, abstract el l 120)). Luminal B breast cancer has a poor prognosis within the family of ER+ breast cancers. In particular, unlike Luminal A breast cancer, prognosis does not appear to be improved with standard of care anti-hormonal therapies. Luminal B breast cancers are also associated with up-regulation of the PI3K pathway (Creighton et al, 2010, supra). Therapy of early (Stage 1 or 2) breast cancer is generally surgical (lumpectomy or mastectomy). After surgery, most patients will receive adjuvant therapy to prevent recurrence. The majority (80-95%) of patients with ER+ tumors receive hormonal therapy. Patients with higher stage and/or high histological grade tumors generally receive along with hormonal therapy. Thus, anti-hormonal therapy (targeting estrogen) is administered in several breast cancer settings. Following initial hormonal therapy, 66% of patients with Stage 1 to 3 diseases will have a recurrence with metastatic disease. Hormonal therapy is the first-line regimen of choice in ER+ recurrent disease. Currently, non-steroidal aromatase inhibitors, such as anastrazole and letrozole, are the most commonly used anti-hormonal agents in the first line metastatic setting. Use of steroidal aromatase inhibitors, such as exemestane, is increasing in this setting, especially in patients who have previously received anti-hormonal adjuvant therapy. Response to anti-hormonal therapy in the first line advanced cancer setting (metastatic or recurrent) is considered good with objective response rates of 20-25% and progression free survival of approximately 10-12 months. However, the efficacy of anti-hormonal therapy becomes progressively worse as the patient's tumors become increasingly resistant to the therapy. Upon progression with anti-hormonal therapy, various chemotherapeutic options are used to extend a patient's survival. As noted above, a Phase I clinical study has shown a preliminary signal of anti tumor activity in breast cancer patients treated with the mTOR inhibitor, ridaforolimus, and the IGF-IR inhibitor, dalotuzumab (Ebbinghaus, S., "Dual inhibition of mTOR and IGF1R pathways," Abstract CN02-02, AACR-NCI-EORTC International Conference: Molecular

Targets and Cancer Therapeutics, Nov. 12-16, 201 1, San Francisco, CA). The activity signal appeared to derive predominantly from patients with ER+ and high proliferation (based on assessment of Ki67 from the primary tumor) luminal B-like tumors that were refractory to endocrine therapy. Without being bound by any particular theory, several features of luminal B breast cancer may explain the responsiveness of this tumor type to the ridaforolimus- dalotuzumab combination. IGF-IR overexpression has been reported in association with tamoxifen resistance in pre-clinical models, and data from clinical breast cancer specimens suggest that both the IGF-1 ligand and IGF-IR tend to be highly expressed in ER+ high proliferation or luminal B breast cancers. Pre-clinical studies suggest that RAS pathway activity correlates with resistance to ridaforolimus, and among breast cancer subtypes, RAS pathway activity is highest in triple negative disease, a subtype that is relatively resistant to ridaforolimus in pre-clinical studies. In contrast, ER+ high proliferation breast cancer is generally low in RAS pathway activity and tends to be more responsive to ridaforolimus. These observations lead to a hypothesis that ER+ high proliferation breast cancer is characterized by features indicative of high PI3K activity, relatively low utilization of ER leading to endocrine resistance, high expression of IGF-IR family members, and low RAS pathway activity, rendering this tumor type susceptible to dual inhibition of IGF-IR and mTOR pathways with the ridaforolimus- dalotuzumab combination. Thus, the instant invention further relates to a method of treating ER+ breast cancer in a subject suffering there from (e.g., a human subject diagnosed with breast cancer cells expressing the estrogen receptor), including but not limited to ER+ breast cancer with an increased rate of proliferation (i.e., Luminal B-like breast cancer), comprising administering to said subject/patient a therapeutically effective amount of an mTOR inhibitor, an anti-IGF-lR antibody, and an aromatase inhibitor, wherein the mTOR inhibitor is rapamycin, a rapamycin analog selected from ridaforolimus, everolimus or temsirolimus, or a combination thereof, the anti-IGF-lR antibody is selected from dalotuzumab, robatumumab, figitumumab, cixutumumab, ganitumab, Roche R1507 and EM 164, and the aromatase inhibitor is selected from letrozole, exemestane, fulvestrant or anastrozole. In a further embodiment of this portion of the instant invention, the subject/patient is treated by administering a therapeutically effective amount of a rapamycin analog selected from ridaforolimus, everolimus or temsirolimus ridaforolimus, the anti-IGF-lR antibody that is dalotuzumab, and an aromatase inhibitor selected from exemestane and anastrozole. In another embodiment, the subject/patient is treated by administering a therapeutically effective amount of ridaforolimus, dalotuzumab and exemestane. In an embodiment, the mTOR inhibitor, including but not limited to ridaforolimus, that is administered as part of the treatment methods of the invention is given at a daily dose between 7.5 mg and 40 mg. In another embodiment, the daily dose is 10 mg. In a further embodiment, the daily dose is 20 mg. In one embodiment, the mTOR inhibitor, including but not limited to ridaforolimus, is administered to the subject five times a week, including but not limited to five consecutive days with therapy followed by two consecutive days without therapy. In an embodiment, the anti-IGF-lR antibody, including but not limited to dalotuzumab, that is administered as part of the present treatment methods is given intravenously at a dose of 10 mg/kg. In another embodiment of the invention, the anti-IGF-lR antibody is administered once a week. In a further embodiment of the invention, the anti-IGF-lR antibody is administered once every other week. In one embodiment, letrozole is administered as part of the treatment methods of the present invention. The dose of letrozole may be from about 1 mg/day to about 5 mg/day. In another embodiment, the dose of letrozole is about 2.5 mg/day. In another embodiment, exemestane is administered as part of the treatment methods of the present invention. The dose of exemestane may be from about 10 mg/day to about 40 mg/day. In another embodiment, the dose of exemestane is about 25 mg/day. In yet another embodiment, anastrozole is administered as part of the treatment methods of the present invention. The dose of anastrozole may be about 0.5 mg/day to about 3 mg/day. In another embodiment, the dose of anastrozole is about 1 mg/day. In one embodiment, the aromatase inhibitor is given once daily. Accordingly, the present invention relates to methods of treating breast cancer, including ER+ breast cancer having an increased proliferation rate, in subjects suffering there from comprising administering a therapeutic amount of a triplet combination of an mTOR inhibitor, an anti-IGF-lR antibody, and an aromatase inhibitor, wherein the patient is administered within a one week period the following: 10 mg ridaforolimus for 5 consecutive days of the week, 10 mg/kg dalotuzumab, and 25 mg exemestane per day. In a further embodiment of this portion of the invention, 20 mg of ridaforolimus is administered for 5 consecutive days of the week, 10 mg/kg dalotuzumab, and 25 mg exemestane per day. The mTOR inhibitor, the anti-IGF-lR antibody and the aromatase inhibitor can be prepared for simultaneous, separate or successive administration. As used herein, the term "cancer" refers to a disease involving cells that have the potential to metastasize to distal sites and exhibit phenotypic traits that differ from those of non-cancer cells. Cancer cells acquire a characteristic set of functional capabilities during their development, albeit through various mechanisms. Such capabilities include evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion/metastasis, limitless replicative potential, and sustained angiogenesis. The term "cancer cell" is meant to encompass both pre-malignant and malignant cancer cells. The term "breast cancer," as used herein, refers to non-invasive or invasive cancer of the breast as diagnosed by a physician using one or more diagnosis methods/tests, including but not limited pathology reports, blood tests, imaging test, and visible inspection. Breast cancer diagnosis usually accompanies a particular "stage" of the cancer. The cancer stage is based on four characteristics: (1) size of the cancer; (2) whether the cancer is invasive or non-invasive; (3) whether the cancer is in the lymph nodes; and (4) whether the cancer has spread to other parts of the body beyond the breast. Stage is usually expressed as a number on a scale of 0 through 4 - with stage 0 describing non-invasive cancers that remain within their original location (such as ductal carcinoma in situ (DOS)) and stage 4 describing invasive cancers that have spread outside the breast to other parts of the body (such as lungs, distant lymph nodes, skin, bones, liver or brain). The term "locally advanced" or "regionally advanced" are used to describe stage 4 invasive breast cancer, referring to large tumors that involve the breast skin, underlying chest structures, changes to the breast's shape, and/or lymph node enlargement that is visible or palpable. Breast cancer may be stage 4 at first diagnosis or can be recurrence of a previous breast cancer that has spread to other parts of the body. The term "treatment of breast cancer" or "treating breast cancer," as referred to herein, means one or more of the following: amelioration of breast cancer symptoms, inhibition and/or reduction of the growth or metastasis rate of breast cancer cells, reduction in tumor volume, and/or prevention or delayed onset of recurrence. Therefore, the methods described herein may be used to reduce the proliferation of cancer cells, increase the death of cancer cells, and/or reduce the size of a tumor or spread of a tumor in a patient. The terms are not meant to be absolute, referring instead to amelioration of breast cancer symptoms, etc., relative to an appropriate control. The methods of the present invention may be used to treat any of the stages of breast cancer (stage 0, stage 1, stage 2, stage 3, and/or stage 4). The pharmaceutically active agents administered as part of the treatment methods of the present invention may be given either prior to or following surgical removal of primary tumors and/or treatment such as administration of radiotherapy or conventional chemotherapeutic drugs. In one embodiment, the patient having breast cancer has already failed other treatment regimens such as chemotherapy, or for whom cancer is recurring. In another embodiment, the patient is in remission. In one embodiment, the methods of the present invention are used to treat women diagnosed with breast cancer who are post-menopausal (i.e., woman who have experienced 12 consecutive months without menstruation). In another embodiment, the treatment methods are used to treat women diagnosed with breast cancer who are pre-menopausal. In one embodiment, the treatment methods are used to treat breast cancers having one or more of the following characteristics: estrogen receptor positive (ER+), HER2 negative (HER2-), and/or increased proliferation positive ("high proliferation"). In another embodiment, the treatment methods of the present invention are used to treat breast cancers that are characterized as ER+, HER2- and high proliferation. In another embodiment, the treatment methods of the present invention may reduce the size of a breast tumor or the spread of a breast cancer cells in a patient by at least 5 percent, at least 10 percent, at least 15 percent, at least 20 percent, at least 25 percent, at least 30 percent, at least 35 percent, at least 40 percent, at least 45 percent, at least 50 percent, at least 55 percent, at least 60 percent, at least 65 percent, at least 70 percent, at least 75 percent, at least 80 percent, at least 85 percent, at least 90 percent, at least 95 percent or at least 99 percent relative to a control such as PBS, as determined by standard imaging techniques. The treatment methods described herein may increase survival of the patient by 1month, 2 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more, as determined by standard statistical methods; may render the subject disease-free; and/or may prevent the progression from non-invasive to invasive breast cancer. Methods for determining estrogen receptor positivity of tumors are known in the art. For example, estrogen receptor protein can be measured as femtomoles per milligram of cytosol protein. In this assay, values above 10 are positive, values from 3 to 10 are intermediate, and values less than 3 are negative. Other assays known in the art can be used to determine if the breast cancer is estrogen receptor positive, in particular assays based on antibodies to estrogen receptors alpha and beta and their use in biochemical or histological assays. At minimum, estrogen receptor positivity is defined as greater than one percent tumor cells positive as determined by immunohistochemistry (IHC), irrespective of intensity (see, Goldhirsch, A. et al, 2009, Ann. Oncol 20:1319-1329). Methods for determining the HER2 status of tumors are known in the art, including using IHC or fluorescence in situ hybridization (FISH). As an example, HER2 negative status can be assigned by finding no fluorescence by FISH or less than 3+ fluorescence by IHC (see, Mrozkowiak, A. et al, 2004, Pol. J. Pathol. 55:165-171; Yeh, I., 2002, Am. J. Clin. Pathol. 117(Suppl 1):S26-S35). Methods for determining high proliferation of breast cancer are known in the art, including but not limited to determining proliferation status based on a variety of RNA based signatures {e.g., GGI, GFS, Ki67, and/or PPH3 expression). Immunohistochemical assessment of markers of proliferations may be used to determine proliferation status (see, Williams, D.J. et al, 201 1, Appl. Immunohistochem. Mol. Morphol. 19:431-436). Ki67 has been cleared by the FDA as a marker of proliferative activity of normal and neoplastic breast tissue (Kl 11755 test). Many different RNA signatures exist as markers for proliferation, status and/or stage (Oncotype DX, MammaPrint, and PAM50). In one embodiment, high proliferation tumors are determined by measuring the Ki67 labeling index as having greater than or equal to 15%. The methods and compositions of the present invention may be used in combination with one or more additional treatment regimens for breast cancer. Treatments for breast cancer are well known in the art and continue to be developed. Treatments include but are not limited to surgery, including axillary dissection, sentinel lymph node biopsy, reconstructive surgery, surgery to relieve symptoms of advanced cancer, lumpectomy (also called breast conservation therapy), partial (segmental) mastectomy, simple or total mastectomy, modified radical mastectomy, and radical mastectomy; ; bone marrow transplantation; peripheral blood stem cell therapy; bisphosphonates; additional chemotherapy agents; radiation therapy; additional hormonal therapy; acupressure; and acupuncture. Any combination of therapies may be used in conjunction with the methods of the present invention. mTOR Inhibitors There are many mTOR inhibitors in clinical development and/or approved for treatment of various human malignancies that are structural analogs of rapamycin. The mTOR inhibitors that may be used in the treatment methods of the instant invention include rapamycin, ridaforolimus, temsirolimus, everolimus, and additional rapamycin-analogs. Ridaforolimus, also known as AP 23573, MK-8669 and deforolimus, has the following structure:

Ridaforolimus is a non-prodrug analog of rapamycin (sirolimus) that has anti proliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models utilizing human tumor cell lines. Ridaforolimus has been administered to patients with advanced cancer and is currently in clinical development for various advanced malignancies, including but not limited to studies in patients with advanced soft tissue or bone sarcomas and non-small cell lung cancer. Ridaforolimus is generally well-tolerated with a predictable and manageable adverse event profile, and possess anti-tumor activity in a broad range of cancers. Ridaforolimus can be made by the following process: To a cooled (0°C) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane is added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The cold (0°C) reaction solution is diluted with ~20 mL ethyl acetate (EtOAc) and then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHC03 (100 mL). The aqueous layer is removed, the organic layer is washed with ice cold IN HC1 (1x100 mL), saturated NaHCO3(lxl00 mL), and brine (1x100 mL), then dried over MgS04 and concentrated. The crude product can be purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane). An alternative method to make ridaforolimus is as follows: Rapamycin and dichloromethane are charged into a nitrogen-purged reaction flask. The stirred solution is cooled to approximately 0°C (an external temperature of -5 ± 5°C is maintained throughout the reaction). A solution of dimethylphosphinic chloride (2.0 molar equivalents) in dichloromethane is added, followed by the addition of a solution of 3,5-lutidine (2.2 molar equivalents) in dichloromethane. Throughout both additions, the internal temperature of the reaction stays below 0°C. The cooled reaction solution is transferred to an extractor containing saturated aqueous NaHC0 3 and methyl -t-butyl ether (MTBE), ethyl acetate or diethyl ether. Reaction progress is monitored by TLC (1:10:3:3 MeOH/DCM/EtOAc/hexanes) and reverse-phase HPLC analyses. The isolated organic layer is successively washed with ice cold IN HC1, saturated aqueous NaHC0 3 (2x), saturated aqueous NaCl, and dried over sodium sulfate. Upon filtration and solvent removal, the residue undergoes solvent exchange with acetone followed by concentration in vacuo to provide crude product, which may be analyzed for purity by normal- and reversed-phase HPLC. Further description and preparation of ridaforolimus is described in U.S. Patent No. 7,091,213 to Ariad Gene Therapeutics, Inc., which is hereby incorporated by reference in its entirety. Temsirolimus, also known as Torisel®, is a water soluble ester of rapamycin and currently marketed by for the treatment of advanced renal cell carcinoma. A description and preparation of temsirolimus is described in U.S. Patent No. 5,362,718 to American Home Products Corporation, which is hereby incorporated by reference in its entirety. Everolimus, also known as Afinitor® or RAD001, marketed by Novartis, has greater stability and enhanced solubility in organic solvents, as well as more favorable pharmacokinetics with fewer side effects, than rapamycin. Everolimus is currently marketed for the treatment of advanced renal cell carcinoma, progressive or metastatic pancreatic neuroendocrine tumors, and subependymal giant cell astrocytoma (SEGA-brain tumor). Everolimus has been used in conjunction with microemulsion cyclosporin (Neoral®, Novartis) to increase the efficacy of the immunosuppressive regime. An mTOR inhibitor that may be used in the treatment methods of the instant invention may also exist as various crystals, amorphous substances, pharmaceutically acceptable salts, hydrates and solvates. Further, an mTOR inhibitor used in the instant invention may be provided as a prodrug {i.e., a functional derivative of an mTOR inhibitor that can be readily converted into a compound needed/used by living bodies). Accordingly, in the methods of treatment of breast cancer in the invention, the term "administration" includes not only the administration of a specific compound but also the administration of a compound which, after administered to patients, can be converted into the specific compound in the living body. Conventional methods for selection and production of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is referred to herein and is entirely incorporated herein as a part of the present description. Metabolites of an mTOR inhibitor compound may include active compounds that are produced by putting the compound in a biological environment, and are within the scope of the compound in the invention. A suitable amount of an mTOR inhibitor is administered to a patient undergoing treatment for breast cancer as per the methods of the present invention. In an embodiment, the mTOR inhibitor is administered in doses from about 7.5 mg - 40 mg per day. In an embodiment of the invention, the mTOR inhibitor is administered in a dose of 7.5 mg per day. In another embodiment of the invention, the mTOR inhibitor is administered in a dose of 10 mg per day. In another embodiment of the invention, the mTOR inhibitor is administered in a dose of 20 mg per day. In another embodiment of the invention, the mTOR inhibitor is administered in a dose of 30 mg per day. In another embodiment of the invention, the mTOR inhibitor is administered in a dose of 40 mg per day. In an embodiment of the invention, the mTOR inhibitor can be administered 5 times per week. For example, ridaforolimus treatment can be started on Day 1, and continued at the specified dosing level for five consecutive days, followed by two days without ridaforolimus treatment. Ridaforolimus can then be continued on this daily X 5 schedule each week.

Anti-IGF-IR Antibodies A anti-IGF-lR antibody used in the treatment methods of the instant invention is an isolated antibody, or functional fragment thereof, wherein said antibody or one of its said fragments is capable of binding specifically to the human insulin-like growth factor 1 receptor ("IGF-1R") and, preferably, capable of inhibiting binding of the ligands insulin growth factor- 1 ("IGF-1" and/or insulin growth factor-2 ("IGF-2") to IGF-IR and/or capable of specifically inhibiting the signaling cascade attendant to the binding of at least one ligand to said IGF-IR receptor. The IGF-IR antibodies that may be used in the treatment methods of the instant invention include monoclonal and/or polyclonal antibodies, although specifically capable of binding IGF-1R. Anti-IGF-IR antibodies that may be used in the instant treatment methods include dalotuzumab (MK-0646; CAS no. 1005389-60-5), robatumumab (SHC 71745), figitumumab (CP-751871), cixutumumab 0MC-A12), ganitumab (AMG479), Roche R1507 and EM164. "Dalotuzumab," "h7C10," "MK-0646," or "F50035" are used interchangeably to describe a that is characterized as binding IGF-1R, as well as binding the IR/IGF-1 hybrid receptor (see, U.S Patent No. 7,241,444 and U.S. Patent No. 7,553,485). Dalotuzumab comprises a light chain comprising three CDRs as set forth by the amino acid sequences of SEQ ID NOs: 1, 2 and 3, and a heavy chain comprising three CDRs as set forth by the amino acid sequences of SEQ ID NOs: 4, 5 and 6. Dalotuzumab is derived from an antibody produced from a murine hybridoma deposited at the Centre National de Culture De Microorganisme (CNCM, National Center of Microorganism Culture) (Institut Pasteur, Paris, France) on September 19, 2001 under the number 1-2717. The monoclonal antibody secreted from this deposited hybridoma is called 7C10. The light chain amino acid sequence of dalotuzumab is set forth in SEQ ID NO: 9, and the heavy chain amino acid sequence is set forth in SEQ ID NO: 10. The variable domain amino acid sequence of dalotuzumab is set forth in SEQ ID NO: 7, and the heavy chain amino acid sequence is set forth in SEQ ID NO: 8. Methods for making and using dalotuzumab are described in U.S. Patent No. 7,241,444 to Pierre Fabre Medicament, which is hereby incorporated by reference in its entirety. Figitumumab, also known as CP-75 1871, is a fully human antibody under investigation by Pfizer. A description and preparation of figitumumab is described in U.S. Patent No. 7,037,498 to Abgenix, Inc and Pfizer, Inc., which is hereby incorporated by reference in its entirety. Cixutumumab, also known as IMC-A12, is a fully human antibody under investigation by ImClone. A description and preparation of cixutumumab is described in U.S. Patent No. U.S. 7,638,605 to ImClone, LLC, which is hereby incorporated by reference in its entirety. Ganitumab, also known as AMG479, is under investigation by , Inc. A description and preparation of Amgen AMG479 is described in U.S. Patent No. 7,871,61 1 to Amgen, Inc., which is hereby incorporated by reference in its entirety. Roche R1507 is under investigation by Hoffmann-LaRoche. A description and preparation of Roche R1507 is described in U.S. Patent No. 7,378,503 to Hoffmann-LaRoche, Inc., which is hereby incorporated by reference in its entirety. EM 164 is under investigation by Immunogen. A description and preparation of EM164 is described in U.S. Patent No. 7,538,195 to Immunogen, Inc., which is hereby incorporated by reference in its entirety In an embodiment of the invention, the anti-IGF-lR antibody used in the methods of the present invention comprises the light chain CDRs and/or the heavy chain CDRs; and/or the light chain variable region and/or the heavy chain variable region of the immunoglobulin chains, and/or the full light chain and/or the full heavy chain, in any of the antibodies selected from dalotuzumab (MK-0646; CAS no. 1005389-60-5), robatumumab (SHC 71745), figitumumab (CP-751871), cixutumumab (IMC-A12), ganitumab (AMG479), Roche R1507 or EM164. In an embodiment of the invention, the anti-IGF-lR antibody comprises a heavy chain comprising one or more CDRs selected from the amino acid sequence as set forth in SEQ ID NOs: 4, 5 and/or 6. In another embodiment, the anti-IGF-lR antibody comprises a light chain comprising one or more CDRs selected from the amino acid sequence selected from SEQ ID

NOs: 1, 2 and/or 3. In a further embodiment, the anti-IGF-lR antibody comprises a heavy chain comprising one or more CDRs selected from the amino acid sequence as set forth in SEQ ID NOs: 4, 5 and/or 6, and a light chain comprising one or more CDRs selected from an amino acid sequence as set forth in SEQ ID NOs: 1, 2 and/or 3. In a still further embodiment of the invention, the heavy chain of the anti-IGF-lR antibody comprises a first, second and third CDR comprising the amino acid sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and the light chain comprises a first, second and third CDR comprising the amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively. In another embodiment, the light chain of the anti-IGF-lR antibody used in the treatment methods of the present invention comprises the amino acid sequence as set forth in SEQ ID NO: 7. In a further embodiment, the heavy chain of the anti-IGF-lR antibody used in the treatment methods of the present invention comprises the amino acid sequence as set forth in SEQ ID NO: 8. In a still further embodiment, the anti-IGF-lR antibody used in the treatment method of the present invention comprises a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 7 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 8. In another embodiment, the light chain of the anti-IGF-lR antibody used in the methods of the present invention comprises the amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the light chain consists of the amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the heavy chain of the anti-IGF-lR antibody used in the methods of the present invention comprises the amino acid sequence as set forth in SEQ ID NO: 10. In a further embodiment, the light chain consists of the amino acid sequence as set forth in SEQ ID NO: 10. In another embodiment, the light chain of the anti-IGF-lR antibody used in the methods of the present invention comprises a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 10. In a further embodiment, the anti-IGF-lR antibody used in the methods of the present invention is dalotuzumab, consisting of a light chain amino acid sequence as set forth in SEQ ID NO: 9 and a heavy chain amino acid sequence as set forth in SEQ ID NO: 10. An anti-IGF-lR antibody derived from dalotuzumab may be used in the methods of the present invention and may contain a light chain comprising one or more CDRs whose sequence has at least 80%, preferably 85%, 90%>, 95% and 98% identity, after optimum alignment, with the amino sequences as set forth in SEQ ID NOs: 1, 2 and/or 3, and/or a heavy chain comprising one or more CDRs whose sequence has at least 80%, preferably 85%, 90%, 95% and 98% identity, after optimum alignment, with the amino acid sequences as set forth in SEQ ID NOs: 4, 5 and/or 6. Further, anti-IGF-lR antibodies derived from dalotuzumab that may be used in the methods of the present invention may comprise a light chain comprising a variable domain having least 80% identity after optimum alignment with the amino acid sequence as set forth in SEQ ID NO: 7, and/or a heavy chain comprising a variable domain having at least 80% identity after optimum alignment with the amino acid sequence as set forth in SEQ ID NO: 8. Likewise, anti-IGF-lR antibodies derived from dalotuzumab that may be used in the methods of the present invention may comprise a light chain having least 80% identity after optimum alignment with the amino acid sequence as set forth in SEQ ID NO: 9, and/or a heavy chain having at least 80% identity after optimum alignment with the amino acid sequence as set forth in SEQ ID NO: 10. In an embodiment of the invention, the anti-IGF-lR antibody or antigen-binding fragment is a monoclonal antibody, a recombinant antibody, a labeled antibody, a bivalent antibody, a polyclonal antibody, a bispecific antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, a bispecific antibody, a camelized single domain antibody, a diabody, an scfv, an scfv dimer, a dsfv, a (dsfv)2, a dsFv-dsfv', a bispecific ds diabody, an Fv, a nanobody, an Fab, an Fab', an F(ab') 2, or a domain antibody; or any of the foregoing that comprises any of the CDRs and/or heavy chain variable regions and/or light chain variable regions of the antibodies discussed herein, including dalotuzumab (MK-0646), robatumumab (SHC 71745), figitumumab (CP-751871), cixutumumab (IMC-A12), ganitumab (AMG479), Roche R1507 and EM164). Reference to "isolated" indicates a different form than found in nature. The different form can be, for example, a different purity than found in nature and/or a structure that is not found in nature. "Isolated" anti-IGF-lR antibodies, and any nucleic acid molecules encoding said antibody proteins, will be free or substantially free of either material with which they are naturally associated, such as other polypeptides or nucleic acids found in their natural environment (e.g. , serum proteins), or material in the environment in which they are prepared (e.g., cell culture) when such preparation is by recombinant DNA technology (practiced in vitro) or in vivo. A structure not found in nature includes recombinant structures where different regions are combined. This includes, for example, humanized antibodies where one or more murine complementarity determining region is inserted onto a human framework scaffold or a murine antibody is resurfaced to resemble the surface residues of a human antibody, hybrid antibodies where one or more complementarity determining region from an anti-IGF-lR antibody is inserted into a different framework scaffold, and antibodies derived from natural human sequences where genes coding for light and heavy variable domains are randomly combined together. A "variable region" has the structure of an antibody variable region from a heavy or light chain. Antibody heavy and light chain variable regions contain three complementarity determining regions ("CDRs") interspaced onto a framework ("FW"). The CDRs are primarily responsible for recognizing a particular epitope. It is well known that epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. Complementarity determining region (or "CDR") is intended to indicate the hypervariable regions of the heavy and light chains of the immunoglobulins as defined by Kabat et al. (Kabat et al., Sequences of proteins of immunological interest, 5th Ed., U.S. Department of Health and Human Services, NIH, 1991, and later editions). Conventional antibodies contain three heavy chain CDRs and three light chain CDRs. The term CDR or CDRs is used here in order to indicate, according to the case, one of these regions or several, or even the whole, of these regions which contain the majority of the amino acid residues responsible for the binding by affinity of the antibody for the antigen or the epitope which it recognizes. Reference to "protein" indicates a contiguous amino acid sequence and does not provide a minimum or maximum size limitation. One or more amino acids present in the protein may contain a post-translational modification, such as glycosylation or disulfide bond formation. The antibodies according to the present invention are preferably specific monoclonal antibodies, especially of murine, chimeric or humanized origin, which can be obtained according to the standard methods well known to the person skilled in the art. Reference to a "monoclonal antibody" indicates a collection of antibodies having the same, or substantially the same, complementarity determining region and binding specificity. The variation in the antibodies is that which would occur if the antibodies were produced from the same construct(s). In general, for the preparation of monoclonal antibodies or their functional fragments, especially of murine origin, it is possible to refer to techniques which are described in particular in the manual "Antibodies" (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor NY, pp. 726, 1988) or to the technique of preparation from hybridomas described by Kohler and Milstein (Nature, 256:495-497, 1975). Monoclonal antibodies can be produced, for example, from a particular murine hybridoma generated from the fusion of mouse myeloma and mouse spleen cells and from a recombinant cell containing one or more recombinant genes encoding the antibody. The antibody may be encoded by more than one recombinant gene wherein, for example, one gene encodes the heavy chain and one gene encodes the light chain. Monoclonal antibodies used in the treatment methods of the present invention can be obtained, for example, from an animal cell immunized against the IGF-1 receptor, or one or more fragments thereof that contain an epitope of interest or an epitope that is specifically recognized by a known anti-IGF-lR antibody. Said IGF-1 receptor, or one of its said fragments, can be produced according to standard methods, including genetic recombination starting with a nucleic acid sequence containing a cDNA sequence encoding the receptor or fragment or by peptide synthesis starting from a sequence of amino acids comprised in the peptide sequence of the receptor/fragment. The antibodies can be purified on an affinity column on which the IGF-1 receptor or one of its fragments containing the epitope specifically recognized by said antibodies has been immobilized. In particular, said monoclonal antibodies can be purified by chromatography on protein A and/or G, followed or not by ion-exchange chromatography aimed at eliminating residual protein contaminants, as well as any DNA and/or LPS, and further followed or not by exclusion chromatography on Sepharose gel in order to eliminate potential dimer or multimer aggregates. The whole of these techniques can be used simultaneously or successively. A "chimeric antibody" is a monoclonal antibody constructed from variable regions derived from a different organism from the constant regions. For example, a chimeric antibody can contain variable regions from a murine source and constant regions derived from the intended host source (e.g., human; for a review, see Morrison and Oi, 1989, Advances in Immunology 44: 65-92). To this end, the artisan may use known techniques to generate a chimeric antibody with the binding characteristics of a known anti-IGF-lR antibody and/or an anti-IGF-lR antibody as described herein (supra). For example, the variable light and heavy genes from a rodent (e.g., mouse) antibody can be cloned into mammalian expression vectors which contain the appropriate human light chain and heavy chain constant domain coding regions, respectively. These heavy and light chain "chimeric" expression vectors are then cotransfected into a recipient cell line and subjected to known cell culture techniques, resulting in production of both the light and heavy chains of a chimeric antibody. Such chimeric antibodies have historically been shown to have the binding capacity of the original rodent monoclonal while significantly reducing immunogenicity problems upon host administration. A "humanized antibody" further reduces the chance of a patient mounting an immune response against a therapeutic antibody when compared to use, for example, of a chimeric or fully murine monoclonal antibody. The strategy of "humanizing" involves sequence comparison between the non-human and human antibody variable domain sequences to determine whether specific amino acid substitutions from a non-human to human consensus is appropriate (Jones et al, 1986, Nature 321 : 522-526). This technology is well known in the art and is represented by numerous strategies for its improvement, including but not limited to, "reshaping" (see Verhoeyen, et al, 1988, Science 239:1534-1536), "hyperchimerization" (see Queen, et al, 1991, Proc. Natl. Acad. Sci. 88:2869-2873), "CDR grafting" (Winter and Harris, 1993, Immunol. Today 14:243-246), "veneering" (Mark, et al, 1994, Derivation of

Therapeutically Active Humanized and Veneered anti-CD 18 Antibodies . In: Metcalf and Dalton, eds. Cellular Adhesion: Molecular Definition to Therapeutic Potential. New York: Plenum Press, 291-312), and "SDR grafting" (Kashmiri et al, 2005, Methods 36:25-34). Fully human mAbs can be produced using genetically engineered mouse strains which possess an immune system whereby the mouse antibody genes have been inactivated and in turn replaced with a repertoire of functional human antibody genes, leaving other components of the mouse immune system unchanged. Such genetically engineered mice allow for the natural in vivo immune response and affinity maturation process, resulting in high affinity, fully human monoclonal antibodies. This technology is well known in the art and is fully detailed in various publications, including but not limited to U.S. Patent Nos. 5,939,598; 6,075,181; 6,1 14,598; 6,150,584 and related family members; as well as U.S. Patent Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877, 397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429. See also a review from Kellerman and Green, 2002, Curr. Opinion in Biotechnology 13: 593- 597. Human antibodies can also be produced starting with a human phage display library. Antibodies used as part of the treatment methods of the present invention may be functional antibody fragments, such as Fv, scFv (sc is "single chain"), Fab, F(ab') 2, Fab', scFv- Fc fragments or diabodies, or any fragment of which the half-life time would have been increased by chemical modification, such as the addition of poly(alkylene) glycol such as poly(ethylene) glycol ("PEGylation") (pegylated fragments called Fv-PEG, scFv-PEG, Fab-PEG,

F(ab') 2-PEG or Fab'-PEG) ("PEG" for polyethylene glycol), or by incorporation in a liposome. Preferably, these functional fragments will generally have the same specificity of binding as the antibody from which they are descended, including but not limited to dalotuzumab. Antibody fragments used in the methods of the invention can be obtained by starting from antibodies such as those described herein by methods such as digestion by enzymes, such as pepsin or papain, and/or by cleavage of the disulfide bridges by chemical reduction. In another manner, antibody fragments can be obtained by techniques of genetic recombination well known to the person skilled in the art or else by peptide synthesis by means of, for example, automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc. Any functional antibody fragment used in the treatment methods of the present invention will be constituted or will comprise a partial sequence of the heavy or light variable chain of the antibody from which it is derived (including, but not limited to, dalotuzumab), said partial sequence being sufficient to retain the same specificity of binding as the antibody from which it is descended and a sufficient affinity, preferably at least equal to 1/100, in a more preferred manner to at least 1/10, of that of the antibody from which it is descended, with respect to the IGF-1 receptor. Such a functional fragment will contain at the minimum 5 amino acids, preferably 10, 15, 25, 50 and 100 consecutive amino acids of the sequence of the antibody from which it is descended. In one embodiment, said functional fragment has one or more of the characteristic CDRs set forth in the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5 and/or 6, and, especially, in that it is capable of exerting in a general manner an even partial activity of the antibody from which it is descended (dalotuzumab), such as in particular the capacity to recognize and to bind to the IGF-1 receptor, and, if necessary, to inhibit the activity of the receptor. "Percentage of identity" between two nucleic acid or amino acid sequences is intended to indicate a percentage of identical nucleotides or amino acid residues between the two sequences to be compared, obtained after the best alignment (optimum alignment), this percentage being purely statistical and the differences between the two sequences being distributed randomly and over their entire length. The comparisons of sequences between two nucleic acid or amino acid sequences are traditionally carried out by comparing these sequences after having aligned them in an optimum manner, said comparison being able to be carried out by segment or by "comparison window." The optimum alignment of the sequences for the comparison can be carried out, in addition to manually, by means of the local homology algorithm of Smith and Waterman (1981) [Ad. App. Math. 2:482], by means of the local homology algorithm of Neddleman and Wunsch (1970) [J. Mol. Biol. 48: 443], by means of the similarity search method of Pearson and Lipman (1988) [Proc. Natl. Acad. Sci. USA 85:2444), by means of computer software using these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI, or else by BLAST N or BLAST P comparison software). The percentage of identity between two nucleic acid or amino acid sequences is determined by comparing these two sequences aligned in an optimum manner and in which the nucleic acid or amino acid sequences to be compared can comprise additions or deletions with respect to a reference sequence for optimum alignment between the sequences. The percentage of identity is calculated by determining the number of identical positions for which the nucleotide or the amino acid residues are identical between the two sequences, by dividing this number of identical positions by the total number of positions in the comparison window and by multiplying the result obtained by 100 in order to obtain the percentage of identity between these two sequences. As described herein, an amino acid sequence having at least 80%, preferably

85%, 90% , 95%o and 98%> identity with a reference amino acid sequence preferably contains a deletion, addition or substitution of at least one amino acid with respect to the reference sequence. In the case of a substitution of one or more consecutive or nonconsecutive amino acid(s), preferred substitutions are those in which the substituted amino acids are replaced by "equivalent" amino acids. The expression "equivalent amino acids" indicates any amino acid capable of being substituted with one of the amino acids of the base structure without, however, essentially modifying the biological activities of the corresponding antibodies. Equivalent amino acids can be determined either by relying on their structural homology with the amino acids which they replace, or on results of comparative trials of biological activity between the different antibodies capable of being carried out. By way of example, equivalent amino acid substitutions include, but are not limited to, replacing leucine by valine or isoleucine, aspartic acid by glutamic acid, glutamine by asparagine, and arginine by lysine. The reverse substitutions can be naturally envisioned under the same conditions. By nucleic acid, nucleic or nucleic acid sequence, polynucleotide, oligonucleotide, polynucleotide sequence, nucleotide sequence, terms which will be employed indifferently in the present invention, it is intended to indicate a precise linkage of nucleotides, which are modified or unmodified, allowing a fragment or a region of a nucleic acid to be defined, containing or not containing unnatural nucleotides, and being able to correspond just as well to a double-stranded DNA, a single-stranded DNA as to the transcription products of said DNAs. Monoclonal antibodies can be produced, for example, from a particular murine hybridoma generated from the fusion of mouse myeloma and mouse spleen cells and from a recombinant cell containing one or more recombinant genes encoding the antibody. The antibody may be encoded by more than one recombinant gene wherein, for example, one gene encodes the heavy chain and one gene encodes the light chain. Recombinant nucleic acid encoding an anti-IGF-lR antibody can be expressed in a host cell that, in effect, serves as a factory for the encoded protein. The recombinant nucleic acid can provide a recombinant gene encoding the anti-IGF-lR antibody that exists autonomously from a host cell genome or as part of the host cell genome. A recombinant gene contains nucleic acid encoding a protein along with regulatory elements for protein expression. Generally, the regulatory elements that are present in a recombinant gene include a transcriptional promoter, a ribosome binding site, a terminator, and an optionally present operator. A promoter is defined as a DNA sequence that directs RNA polymerase to bind to DNA and initiate RNA synthesis. A strong promoter is one which causes mRNAs to be initiated at high frequency. A preferred element for processing in eukaryotic cells is a polyadenylation signal. Antibody associated introns may also be present. Examples of expression cassettes for antibody or antibody fragment production are well known in art. (E.g., Persic et al, 1997, Gene 187:9-18; Boel et al, 2000, J. Immunol. Methods 239:153-166; Liang et al, 2001, J. Immunol. Methods 247:1 19-130; Tsurushita et al, 2005, Methods 56:69-83.) The degeneracy of the genetic code is such that, for all but two amino acids, more than a single codon encodes a particular amino acid. This allows for the construction of synthetic DNA that encodes a protein where the nucleotide sequence of the synthetic DNA differs significantly from the nucleotide sequences disclosed herein, but still encodes such a protein. Such synthetic DNAs are intended to be within the scope of the present invention. If it is desired to express DNAs in a particular host cell or organism, the codon usage of such DNAs can be adjusted to maximize expression of a protein. One approach is to choose codons that reflect the codon usage of that particular host. Expression of a recombinant gene in a cell is facilitated using an expression vector. Expression vectors are defined herein as DNA sequences that are required for the transcription of cloned DNA and the translation of their mRNAs in an appropriate host. Such vectors can be used to express eukaryotic DNA in a variety of hosts such as bacteria, blue green algae, plant cells, insect cells and animal cells. Specifically designed vectors allow the shuttling of DNA between hosts such as bacteria-yeast or bacteria-animal cells. Preferably, the expression vector, in addition to a recombinant gene, also contains an origin of replication for autonomous replication in a host cell, a selectable marker, a limited number of useful restriction enzyme sites, and a potential for high copy number. Examples of expression vectors for antibody and antibody fragment production are well known in art (e.g., Persic et al, 1997, Gene 187:9-18; Boel et al, 2000, J. Immunol. Methods 239:153-166; Liang et al, 2001, J. Immunol. Methods 247:1 19-130; Tsurushita et al, 2005, Methods 5(5:69-83). Expression vectors may include, but are not limited to, cloning vectors, modified cloning vectors, specifically designed plasmids or viruses. Such expression vectors, including mammalian, bacterial, fungal {e.g., Pichia), and insect cell expression vectors, are commercially available. If desired, nucleic acid encoding an antibody may be integrated into the host chromosome using techniques well known in the art. {E.g., Ausubel, Current Protocols in Molecular Biology, John Wiley, 2005; Marks et al., International Application Number WO 95/17516, International Publication Date June 29, 1995.) A variety of different cell lines can be used for production of recombinant anti- IGF-1R antibody expression, including those from prokaryotic organisms {e.g., E. coli, Bacillus sp, and Streptomyces sp. (or streptomycete)) and from eukaryotic organisms {e.g., yeast, Baculovirus, and mammalian, including but not limited to cell lines of bovine, porcine, monkey and rodent origin) (see, e.g., Breitling et al, Recombinant Antibodies, John Wiley & Sons, Inc. and Spektrum Akademischer Verlag, 1999; Kipriyanov et al, 2004, Molecular Biotechnology 26:39-60; Tsurushita et al, 2005, Methods 36:69-83). Such cell lines are commercially available. Preferred hosts for recombinant anti-IGF-lR antibody expression provide for mammalian post-translational modifications. Post-trans lational modifications include chemical modification such as glycosylation and disulfide bond formation. Another type of post- translational modification is signal peptide cleavage. Glycosylation can be important for some antibody effector functions. (Yoo et al., 2002, Journal of Immunological Methods 261:1 -20; Presta, 2006, Advanced Drug Delivery Reviews 55:640-656; Satoh et al., 2006, Expert Opin. Biol. Ther. 6:1 161-1 173.) Mammalian host cells can be modified, for example, to effect glycosylation. (Yoo et al, 2002, supra; Persic et al, 1997, Gene 187:9-18; Presta, 2006, supra; Satoh et al, 2006, supra.) Non-mammalian cells can also be modified to provide for a desired glycosylation. Glycoengineered Pichia pastoris is an example of such a modified non-mammalian cell. (Li et al., 2006, Nature Biotechnology 24(2):210-215.)

Aromatase Inhibitors Aromatase is a microsomal member of the cytochrome P450 hemoprotein containing enzyme complex superfamily (P450arom, the product of the CYP19 gene) that catalyzes the rate-limiting step in the production of estrogens (the conversion of androstenedione and via three hydroxylation steps to estrone and estradiol, respectively). Aromatase activity is present in many tissues, such as the ovaries, the brain, adipose tissue, muscle, liver, breast tissue, and in malignant breast tumors. The main sources of circulating estrogens are the ovaries in pre-menopausal women and adipose tissue in post-menopausal women. A large number of aromatase inhibitors have been developed and utilized in clinical studies over the last 20 years, mainly for treatment of breast cancer. The expression "aromatase inhibitor" or "Al," as used herein, relates to compounds which inhibit the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively, thus inhibiting estrogen production. Aromatase is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence. The goal of using aromatase inhibitors is typically to reduce the levels of circulating estradiol and to ultimately inhibit the growth of neoplasms that are estrogen receptor positive or estrogen dependent. The high affinity of aromatase inhibitors for aromatase is thought to reside in the -4 nitrogen of the triazole ring that coordinates with the heme iron atom of the aromatase enzyme complex. Aromatase inhibitors are completely absorbed after oral administration with mean half-life of approximately 45 hr (range, 30-60 hr). They are cleared from the systemic circulation mainly by the liver. Gastrointestinal disturbances account for most of the adverse events, although these have seldom limited therapy. Other adverse effects are asthenia, hot flashes, headache, and back pain. The wide clinical safety of aromatase inhibitors, as well as the reduced cost of treatment, makes these agents promising for use in treatment modalities for estrogen dependent disorders, e.g., endometriosis and uterine fibroids. Although these agents are mainly used in post-menopausal women, the success of these agents in inhibiting estrogen production in women of the reproductive age group has been demonstrated. See, e.g., Mitwally, et al, 2000, Reprod. Technol. 10:244-247; Mitwally, et al, 2001, Fertil. Steril. 75:305-9; and Mitwally, et al, 2002, Fertil. Steril. 77:776-80. Aromatase inhibitors have been classified in a number of different ways, including first-, second-, and third-generation; steroidal and nonsteroidal; and by binding activity, i.e., reversible (ionic binding) and irreversible (covalent binding). The most successful, third-generation aromatase inhibitors are now available commercially for breast cancer treatment. Among the aromatase inhibitors that may be used in treatment methods of the present invention, there can be mentioned steroidal inhibitors, including exemestane, formestane, atamestane, and the like, and non-steroidal inhibitors, including fadrozole, letrozole, vorozole, anastrozole, and the like. In general, aromatase inhibitors known in the art are suitable for practicing the present invention. Examples of aromatase inhibitors have been provided above. Some of them, e.g., anastrozole, letrozole and exemestane, may be commercially available, either as a pure compound or in the form of a pharmaceutical composition {e.g., pills for treating breast cancer), while most of them generally can be prepared by methods known in the art. Exemestane is available from Pfizer Inc., New York, N.Y. under the trademark Aromasin® and is a steroidal aromatase inhibitor. Exemestane (6-methylene-androsta-l,4- diene-3,17-dione) is described in more detail in DE Patent 3,622,841, incorporated herein by reference. Exemestane may be administered orally to a human in a dosage range varying from 5 to 200 mg/day, preferably from 10 to 25 mg/day, or parenterally from 50 to 500 mg/day, preferably from 100 to 250 mg/day. Anastrozole is available from AstraZeneca under the trademark Arimidex® (ZN 1033) and is described in more detail in EP 296,749, incorporated herein by reference. Anastrozole is a nonsteroidal aromatase inhibitor. Anastrozole may be administered orally to a human in a dosage range varying from 0.25 to 10 mg/day, preferably from 0.5 to 2.5 mg/day. Letrozole is available from Novartis Pharmaceutical Corporation under the trademark Femara® (CGS 20267) and is described in more detail in EP 236,940, incorporated herein by reference. Letrozole is a nonsteroidal aromatase inhibitor. Letrozole may be administered orally to a human in a dosage range varying from 0.5 to 5 mg/day, preferably from 0.5 to 4 mg/day, most preferably from 1 to 2.5 mg/day. Examples of compositions containing letrozole are well known in the art, see, e.g., Physicians' Desk Reference Copyright (C) 2001 (Medical Economics Company Inc). Anastrozole and letrozole are selective aromatase inhibitors, available for clinical use in North America, Europe and other parts of the world for treatment of post-menopausal breast cancer. These triazole derivatives are reversible, competitive aromatase inhibitors which are highly potent and selective. Their intrinsic potency is considerably greater than that of aminoglutethimide, and at doses of 1-5 mg/day, they inhibit estrogen levels by 97% to >99% in post-menopausal women. This level of aromatase inhibition results in estradiol concentrations below detection by most sensitive immunoassays. Atamestane (l-methyl-androsta-l,4-diene-3,17-dione) is described in more detail in EP Patent 129,500, incorporated herein by reference.

Formestane (4-hydroxy-4-androsten-3,17-dione) and its 4-(C2-Ci2)acyloxy derivative is described in more detail in US Patent No. 4,235,893, incorporated herein by reference. Formestane may be administered parenterally to a human in a dosage range varying from 100 to 500 mg/day, preferably from 250 to 300 mg/day. Fadrozole is described in more detail in EP 165,904, incorporated herein by reference. Finrozole is described in more detail in GB 2,273,704, incorporated herein by reference. The present invention is not limited to the use of the specific aromatase inhibitors named herein; the preparation of other aromatase inhibitors will be apparent to one skilled in the art based on the literature.

Formulations, Routes of Administration and Dosing With regard to the therapeutic pharmaceutical agents used in the methods of the present invention, various preparation forms can be selected, and examples thereof include oral preparations such as tablets, capsules, powders, granules or liquids, or sterilized liquid parenteral preparations such as solutions or suspensions, suppositories, ointments and the like. The mTOR inhibitors may be available as pharmaceutically acceptable salts. The mTOR inhibitors, anti- IGF-IR antibodies, and aromatase inhibitors of the invention are prepared with pharmaceutically acceptable carriers or diluents. The term "pharmaceutically acceptable salt" as referred to in this description means ordinary, pharmaceutically acceptable salt. For example, when the compound has a hydroxyl group, or an acidic group such as a carboxyl group and a tetrazolyl group, then it may form a base-addition salt at the hydroxyl group or the acidic group; or when the compound has an amino group or a basic heterocyclic group, then it may form an acid-addition salt at the amino group or the basic heterocyclic group. The base-addition salts include, for example, alkali metal salts such as sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, Ν ,Ν '-dibenzylethylenediamine salts. The acid-addition salts include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, perchlorates; organic acid salts such as maleates, fumarates, tartrates, citrates, ascorbates, trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates, p-toluenesulfonates. The term "pharmaceutically acceptable carrier or diluent" refers to excipients

(e.g., fats, beeswax, semi-solid and liquid polyols, natural or hydrogenated oils, etc.), water (e.g., distilled water, particularly distilled water for injection, etc.), physiological saline, alcohol (e.g., ethanol), glycerol, polyols, aqueous glucose solution, mannitol, plant oils, additives (e.g., extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant), and the like. Solid preparations can be prepared in the forms of tablet, capsule, granule and powder without any additives, or prepared using appropriate carriers (additives). Examples of such carriers (additives) may include saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; and other conventionally used additives such as gelatin, talc, plant oil and gum arabic. These solid preparations such as tablets, capsules, granules and powders may generally contain, for example, 0.1 to 100% by weight, and preferably 5 to 98% by weight, of the mTOR inhibitor, based on the total weight of each preparation. One or more of the therapeutics agents may be administered parenterally in a form of intramuscular injection, intravenous injection or subcutaneous injection, appropriate solvent or diluent may be exemplified by distilled water for injection, an aqueous solution of lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous glucose solution, ethanol, polyethylene glycol, propylene glycol, liquid for intravenous injection (e.g., an aqueous solution of citric acid, sodium citrate and the like) or an electrolytic solution (for intravenous drip infusion and intravenous injection), or a mixed solution thereof. Such injection may be in a form of a preliminarily dissolved solution, or in a form of powder per se or powder associated with a suitable carrier (additive) which is dissolved at the time of use. The injection liquid may contain, for example, 0.1 to 10% by weight of an active ingredient based on the total weight of each preparation. Liquid preparations are produced in the forms of suspension, syrup, injection and drip infusion (intravenous fluid) using appropriate additives that are conventionally used in liquid preparations, such as water, alcohol or a plant-derived oil such as soybean oil, peanut oil and sesame oil. Liquid preparations such as suspension or syrup for oral administration may contain, for example, 0.1 to 10% by weight of an active ingredient based on the total weight of each preparation. Each preparation in the invention can be prepared by a person having ordinary skill in the art according to conventional methods or common techniques. For example, a preparation can be carried out, if the preparation is an oral preparation, for example, by mixing an appropriate amount of the compound of the invention with an appropriate amount of lactose and filling this mixture into hard gelatin capsules which are suitable for oral administration. On the other hand, preparation can be carried out, if the preparation containing the compound of the invention is an injection, for example, by mixing an appropriate amount of the compound of the invention with an appropriate amount of 0.9% physiological saline and filling this mixture in vials for injection. Suitable dosages are known to medical practitioners and will, of course, depend upon the particular disease state, specific activity of the composition being administered, and the particular patient undergoing treatment. In some instances, to achieve the desired therapeutic amount, it can be necessary to provide for repeated administration, i.e., repeated individual administrations of a particular monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved. Further information about suitable dosages is provided supra. The term "subject" or "patient" or the like refers to a mammal, preferably human, and more preferably are human females. The term "simultaneous" as referred to in this description means that the pharmaceutical preparations of the invention are administered simultaneously in time. The term "separate" as referred to in this description means that the pharmaceutical preparations of the invention are administered at different times during the course of a common treatment schedule. The term "successive" as referred to in this description means that administration of one pharmaceutical preparation is followed by administration of another pharmaceutical preparation; after administration of the first pharmaceutical preparation, the second pharmaceutical preparation can be administered immediately after the first pharmaceutical preparation, or the second pharmaceutical preparation can be administered after an effective time period after the first pharmaceutical preparation; and the effective time period is the amount of time given for realization of maximum benefit from the administration of the first pharmaceutical preparation. The third pharmaceutical preparation is then administered after the second pharmaceutical preparation, either immediately or after an effective time period after the first and/or second pharmaceutical preparation for realization of maximum benefits from the administration of the first and/or second pharmaceutical preparations. The term "administration" and variants thereof {e.g., "administering" a compound) in reference to a therapeutic agent used in the invention means introducing the agent, or a prodrug of the agent, into the system of the subject in need of treatment. When an agent or prodrug thereof is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and sequential introduction of the agent and other agents. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "therapeutically effective amount" is meant a dose that produces therapeutic effects for which it is administered, in the context of the combination therapy in which it is administered. Often, the therapeutically effective or sufficient amount or dose will be lower when administered in the specific combination, than the doses that would be therapeutically effective or sufficient for a monotherapy. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington. The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams and Wilkins). In some embodiments, a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to destroy, modify, control or remove primary, regional or metastatic breast cancer tissue, as described in detail supra. For the present invention, a therapeutically effective amount may refer to the amount of a single therapeutic agent, in combination with the other agents administered to the patient, that is sufficient to delay or minimize the spread of breast cancer. A therapeutically effective amount of a therapeutic agent, in combination with other agents, may also refer to the amount of each therapeutic agent that provides a therapeutic benefit in the treatment or management of breast cancer. In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells. Treatment of breast cancer is further described supra. In some embodiments, a therapeutically effective amount refers to the amount of a therapeutic agent that when administered to a patient in need of such treatment results in, e.g., amelioration of breast cancer symptoms, inhibition and/or reduction of the growth or metastasis rate of breast cancer cells, reduction in tumor volume, and/or prevention or delayed onset of recurrence. The combination therapeutic method as described can be administered to a human patient in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. Intravenous or subcutaneous administration of the antibody is preferred. Combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive (successive) administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities. The clinical dosing of therapeutic combinations of the present invention is likely to be limited by the extent of adverse reactions. In one aspect, a anti-IGF-lR antibody of the invention is administered weekly or may be administered every two to three weeks, at a dose ranged from about 5 mg/kg to about 15 mg/kg. In one embodiment, a dose of letrozole that may be administered as part of the present treatment methods is from about 1 mg/day to about 5 mg/day. In another embodiment, the dose of letrozole is about 2.5 mg/day. In one embodiment, a dose of exemestane that may be administered as part of the present treatment methods is from about 10 mg/day to about 40 mg/day. In another embodiment, the dose of exemestane is about 25 mg/day. In yet another embodiment, a dose of anastrozole that may be administered as part of the present treatment methods is from about 0.5 mg/day to about 3 mg/day. In another embodiment, the dose of anastrozole is about 1 mg/day. In one embodiment, the dosing sequence comprises administering the mTOR inhibitor concurrently with the IGF-IR antibody and the AI. For example, ridaforolimus and the AI can be administered daily while the IGF-IR antibody is administered weekly (e.g., dalotuzumab is administered at a dose of 10 mg/kg i.v weekly, ridaforolimus is administered at 10 mg on a daily schedule, and exemestane is administered at a dose of 25 mg/day; or dalotuzumab is administered at a dose of 10 mg/kg i.v weekly, ridaforolimus is administered at 20 mg on a daily schedule, and exemestane is administered at a dose of 25 mg/day; dalotuzumab is administered at a dose of 10 mg/kg i.v weekly, ridaforolimus is administered at 30 mg on a daily schedule, and exemestane is administered at a dose of 25 mg/day; or dalotuzumab is administered at a dose of 10 mg/kg i.v weekly, ridaforolimus is administered at 40 mg on a daily schedule, and exemestane is administered at a dose of 25 mg/day).

Alternative dosing regimens for the anti-IGF-lR antibody are as follows: (a) 15 mg/kg loading, followed by 7.5 mg/kg every week; (b) 7.5 mg/kg per week; (c) 10.0 mg/kg per week; (d) 7.5 mg/kg every other week; (e) 10.0 mg/kg every other week; (f) 20 mg/kg every other week; (g) 30 mg/kg every three weeks.

All patents, publications and pending patent applications identified are hereby incorporated by reference.

EXAMPLES A combination of ridaforolimus (MK-8669), dalotuzumab (MK-0646) and letrozole was tested in an endocrine sensitive, ER+ breast cancer model. Cell culture - MCF-7 human breast cancer cells stably transfected with the human aromatase gene (MCF-7/AC-1 cells) as previously described (Hou, et al, 201 1, Cancer Res. 1:7597-7607) were routinely maintained in DMEM with 10% FBS, 1% penicillin/streptomycin solution, and 750 mg/mL G418. The culture medium was changed twice weekly. Postmenopausal intratumoral aromatase human xenograft mouse model - Although in vitro culture of established breast cancer cell lines is probably the most widely used model for such pre-clinical evaluation, it is limited in so far as it contains no stromal cells and, as generally used, lacks three-dimensional structure. These limitations make it poorly representative of real cancers. Animal models in which stroma and structure are present should, if they are to be useful, possess genetic and other biomarker abnormalities similar to, if not identical to, their human counterparts. The most direct way to achieve this is to merge human and animal models in the form of heterotransplanted tissues, implanted either heterotopically (subcutaneous) or orthotopically (mammary fad pad). In this experiment, a widely accepted human xenograft model was used, enabling study of the regulation of human cell growth and metastasis in an in vivo environment (see Clarke, R. 1996, Breast Cancer Research and Treatment 39:69-86). There are currently many human xenograft models available for use in breast cancer research, most derived from both established cancer cell lines and spontaneously or genetically engineered immortalized normal breast epithelial cells. One of the more commonly used is the MCF-7 system because of the ease of use and the wealth of information available on this breast cancer cell line from previous in vitro studies (Kim, J.B. et al, 2004, Breast Cancer Res. 6:22-30) Female ovariectomized BALB/c athymic nude mice 4 to 6 weeks of age were obtained from Harlan Laboratories. The animals were housed in a pathogen-free environment under controlled conditions of light and humidity and received food and water. All animal studies were carried out according to the guidelines approved by the Animal Care Committee of the Mayo Clinic, Rochester, MN and by Merck Research Laboratory of Boston. Animals were allowed to acclimatize for 48 hours after shipment before tumor inoculation was done. For inoculation, sub-confluent MCF-7/AC-1 cells were suspended in Matrigel (10 mg/mL) at 2.5 x 107 cells/ mL. Each mouse was injected subcutaneously with 100 mL of cell suspension on each flank. Tumors were measured weekly with calipers, and volumes were calculated with the π 2 formula 4/3 x ri x r2 (rl < r2), in which ri is the smaller radius. Treatments began when the tumors reached a measurable size (250-300 mm3). Mice were randomized to treatment groups using JMP (SAS). MCF7/AC1 cells were used to generate estrogen dependent tumor cells and xenografts with the administration of the aromatase substrate, androstenedione. To enable tumor growth and establishment, androstenedione supplementation was provided in all animals until they grew to approximately 300 mm3 each side (~ 4 weeks). Mice were then treated for 4 weeks with: A : Control (MK-0646 vehicle) 100 ul per week subcutaneously; B : MK-8669, 1 mg/kg IP qd x 5 per week for 4 weeks; C : Letrozole, 10 meg per day SQ for 4 weeks in 0.3% hydroxypropyl cellulose; D : MK-0646, 20 mg/kg/week IP for 4 weeks; E : MK-8669 + MK-0646; F : Letrozole + MK-0646; G : Letrozole + MK-0646 + MK-8669; H : Letrozole+MK-8669 ( 1 mg/kg IP x 5 days weekly) After 7, 14 and 28 days of treatment, tumors were surgically excised from each tumor-bearing animal. At the end of the treatment period, remaining tumor was resected. After each resection, tumors were carefully excised from mouse tissue with portions frozen in OCT medium (Tissue-Tek) or placed in formalin or flash frozen for further analyses. Differences between the groups were analyzed by ANOVA with multiple comparison posttests using Prism (Graph Pad). Western Blot analysis - Western blotting was done as previously described (Hou et al., 201 1, supra). Briefly, proteins were extracted from the tumor tissues by homogenization in buffer containing 50 mmol/L Tris (pH 7.4), 1 mmol/L EDTA, 150 mmol/L NaCl, and protease/phosphatase inhibitors ( 1 mg/mL phenylmethylsulfonyl fluoride, 10 mg/mL aprotinin, and 1 mg/mL leupeptin). The homogenates were centrifuged at 2,000 x g for 15 minutes at 4°C. After centrifugation at 10,000 x g for 5 minutes, the supernatants were separated and their protein concentrations were measured. The protein lysates were separated by 10% SDS-PAGE, transferred onto Immuno-Blot polyvinylidene difluoride membrane (catalog no. 162-0177; Bio- Rad). The membranes were blocked with 5% milk in TBS [10 mmol/L Tris-HCl (pH 8.0) and 150 mmol/L NaCl] plus 0.05% Tween-20 overnight at 4°C and then incubated in 5% milk containing primary antibodies ( 1:1,000/1 ,500 for both antibodies or 1:2,500 dilution for Actin) overnight at 4°C. Antibodies against p-AKT, AKT, p-IGF-IRp, p-MAPK, mitogen activated protein kinase (MAPK) were purchased from Cell SignalingTechnology. Antibody against ERa was purchased from Santa Cruz Biotechnology. After incubation, membranes were washed 3 times (15 minutes each) with 5% milk, incubated with goat anti-rabbit IgG conjugated with HRP

( 1:5,000) in 5% milk for 1 hour at room temperature and washed 3 times (15 minutes each) in TBS. The bands were detected using an ECL Kit (Amersham). Densitometry was done using Genetools software (Syngene). Results - MCF7 cells were modified to express aromatase, so to be sensitive to letrozole therapy. MCF7-Aro cells were grown as xenografted tumors on the flanks of immuno compromised mice and treated as indicated in Figure 2A. Whereas vehicle control tumor size tripled during the 28 day therapy period, letrozole treatment resulted in an average of 19% tumor regression. Addition of dalotuzumab did not increase efficacy of letrozole therapy. However, addition of ridaforolimus to letrozole treatment increased efficacy to 49% tumor regression. Combined ridaforolimus, dalotuzumab and letrozole therapy further increased efficacy to 68% tumor regression, supporting the rationale that ridaforolimus-dalotuzumab in combination with anti-hormonal therapy may be efficacious in ER+ breast cancer. Post-dose analysis of tumor samples in the study is shown in Figure 2B. The Western blot results suggest that ridaforolimus alone ("rida", In 5) or the combination of ridaforolimus and dalotuzumab ("rida/dalo", In 6) resulted in the feedback activation of the ER signaling pathway as measured by the upregulation of progesterone and estrogen receptors. In addition, ridaforolimus upregulated P-AKT and total IGF1R levels. This data confirms that the ridaforolimus/dalotuzumab combination in this breast cancer model effectively targets the oncogenic PI3K signaling pathway and blocks compensatory activation of the ER signaling in tumor cells leading to effective tumor growth inhibition. While a number of embodiments of this invention have been described, it is apparent that the basic examples may be altered to provide other embodiments encompassed by the present invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments, which have been represented by way of example. SEQUENCE LISTING SEQ ID NO: 1 - RSSQSIVHSNGNTYLQ SEQ ID NO: 2 - KVSNRLY SEQ ID NO: 3 - FQGSHVPWT SEQ ID NO: 4 - GGYLWN SEQ ID NO: 5 - YISYDGTNNYKPSLKD SEQ ID NO: 6 - YGRVFFDY SEQ ID NO: 7 1 DIVMTQSPLS LPVTPGEPAS ISCRSSQSIV HSNGNTYLQW YLQKPGQSPQ 51 LLIYKVSNRL YGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSHVP 101 WTFGQGTKVE IK

SEQ ID NO: 8 - 1 QVQLQESGPG LVKPSETLSL TCTVSGYSIT GGYLWNWIRQ PPGKGLEWIG 51 YISYDGTNNY KPSLKDRVTI SRDTSKNQFS LKLSSVTAAD TAVYYCARYG 101 RVFFDYWGQG TLVTVSS

SEQ ID NO: 9 1 DIVMTQSPLS LPVTPGEPAS ISCRSSQSIV HSNGNTYLQW YLQKPGQSPQ 51 LLIYKVSNRL YGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSHVP 101 WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASWCL LNNFYPREAK 151 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 201 VTHQGLSSPV TKSFNRGEC

SEQ ID NO: 10 - 1 QVQLQESGPG LVKPSETLSL TCTVSGYSIT GGYLWNWIRQ PPGKGLEWIG 51 YISYDGTNNY KPSLKDRVTI SRDTSKNQFS LKLSSVTAAD TAVYYCARYG 101 RVFFDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 151 PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSWTVPS SSLGTQTYIC 201 NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 251 LMISRTPEVT CVWDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 301 RWSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 351 LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 401 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK WHAT IS CLAIMED IS: 1. A method of treating breast cancer in a subject suffering there from comprising administering to said subject a therapeutically effective amount of an mTOR inhibitor, an anti-IGF-lR antibody and an aromatase inhibitor, wherein the breast cancer is estrogen receptor positive (ER+), HER2 negative (HER2-) and high proliferation.

2. The method of claim 1, wherein the subject was previously treated with an aromatase inhibitor and subsequently progressed.

3. The method of claim 1, wherein the mTOR inhibitor is a rapamycin analog.

4. The method of claim 3, wherein the mTOR inhibitor is selected from ridaforolimus, temsirolimus, or everolimus.

5. The method of claim 4, wherein the mTOR inhibitor is ridaforolimus.

6. The method of claim 5, wherein on a weekly basis, 10 mg of ridaforolimus is administered for 5 consecutive days.

7. The method of claim 1, wherein the anti-IGF-lR antibody is selected from dalotuzumab, robatumumab, figitumumab, cixutumumab, ganitumab, Roche R1507 and EM 164.

8. The method of claim 1, wherein the anti-IGF-lR antibody comprises at least one light chain and one heavy chain, wherein the light chain comprises three complementarity determining regions (CDRs) as set forth in SEQ ID NO: 1, 2, and 3, respectively, and the heavy chain comprises three CDRs as set forth in SEQ ID NO: 4, 5, and 6, respectively.

9. The method of claim 8, wherein the anti-IGF-lR antibody comprises a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 9, and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 10.

The method of claim 9, wherein the anti-IGF-lR antibody is dalotuzumab. 23235

WO 2013/169611 PCT/US2013/039612

11. The method of claim 10, wherein 10 mg/kg dalotuzumab is administered by intravenous route once per week.

12. The method of claim 1, wherein the aromatase inhibitor is selected from 6 exemestane, anastrozole, letrozole or fulvestrant.

13. The method of claim 1, wherein the aromatase inhibitor is a steroidal inhibitor.

14. The method of claim 13, wherein the aromatase inhibitor is exemestane. 12 15. The method of claim 14, wherein on a weekly basis, 25 mg exemestane is given each day.

16. The method of claim 1, wherein the mTOR inhibitor is ridaforolimus, the anti-IGF-lR antibody is dalotuzumab, and the aromatase inhibitor is exemestane.

18 17. The method of claim 16, wherein on a weekly basis, 10 mg ridaforolimus is given for 5 consecutive days of the week, 10 mg/kg dalotuzumab is administered by intravenous route once per week, and 25 mg exemestane is given each day of the week.

18. The method of claim 1, wherein an ER+ breast cancer has greater than 1% 24 tumor cells positive for the ER as determined by immunohistochemistry.

19. The method of claim 1, wherein a HER2- breast cancer has no fluorescence by fluorescence in situ hybridization or less than 3+ fluorescence by immunohistochemistry.

30 20. The method of claim 1, wherein high proliferation breast cancer has a Ki67 labeling index greater than or equal to 15%.

21. The method of claim 1, wherein the subject is a post-menopausal woman.

INTERNATIONALSEARCH REPORT International application N

PCT/US201 3/03961 2

A . CLASSIFICATION O F SUBJECT MATTER IPC(8) - A61 K 39/395 (201 3.01 ) USPC - 424/1 33.1 According to International Patent Classification (IPC) or to both national classification and IPC

B . FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols) IPC(8) - A61K 39/395, 43/00, 2039/505; A61P 35/00; C07K 16/00; C12Q 1/26, 1/68; C40B 30/04; G01N 33/566 (2013.01) USPC - 424/133.1, 145.1 ; 435/15; 514/177, 182, 217, 249; 506/9 .

Documenlation searched other than minimum documentation to the extent that such documents are included in the Fields searched

CPC - A61K 39/395, 39/39558, 2039/505; G01N 33/57415, 33/6854 (2013.01)

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

PatBase, Google Patents, Google, PubMed

C . DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation of document, with indication, where appropriate, o f the relevant passages Relevant to claim No.

EBBINGHAUS, SCOT. "Dual inhibition of mTOR and IGFR pathways" Molecular Cancer 1-5, 7 Therapeutics, 15 November 201 1 (15.1 1.201 1), AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, Vol. 10, Iss. 1 , Supp.1, Pgs. 1-3. entire document 6 , 8-21

US 2012/0027757 A 1 (SATHYANARAYANAN et al) 02 February 2012 (02.02.2012) entire 6 , 17 document

W O 2012/015741 A2 (SATHYANARAYANAN et al) 02 February 2012 (02.02.2012) entire 8-15 document

JONES et al. "Multicenter, Phase II Trial of Exemestane as Third-Line Hormonal Therapy of 15-17, 2 1 Postmenopausal Women With Metastatic Breast Cancer, 0 1 November 1999 (01 . 1 1.1999), Journal of Clinical Oncology, Vol. 1 , No. 11, Pgs. 3418-25. entire document

NISHIMURA et al. "Ki-67 as a prognostic marker according to breast cancer subtype and a 18-20 predictor of recurrence time in primary breast cancer," Experimental and Therapeutic Medicine, 2 1 July 2010 (21 .07.2010), Vol. 1. No. 5 , Pgs. 747-754. entire document

BASELGA et al. "Everolimus in Postmenopausal Hormone-Receptor - Positive Advanced Breast 1-21 Cancer," The New England Journal of Medicine, 09 February 2012 (09.02.2012), Vol. 366, Pgs. 520-529. entire document

Further documents are listed in the continuation of Box C | |

* Special categories of cited documents: "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than "&" document member of the same patent family the priorit date claimed Date of the actual completion o f the international search Date of mailing of the international search report 12 September 2013 2 S EP 2013

Name and mailing address of the ISA/US Authorized officer: Mail Stop PCT, Attn: ISA/US, Commissioner for Patents Blaine R . Copenheaver P.O. Box 1450, Alexandria, Virginia 22313-1450 Facsimile No. 571-273-3201

Form PCT/lSA/210 (second sheet) (July 2009)