Cellular, Molecular, and Biochemical Targets in Breast Cancer

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1 Cellular, Molecular, and Biochemical Targets in Breast Cancer Kristy Kummerow Ingrid Meszoely December 12, 2012 VUMC Resident Bonus Conference

2 One size fits all surgical treatment of breast cancer Wilhelm Fabricus Hidanus Mastectomy Halstead s Radical Mastectomy Johns Hopkins Hospital Reports, 4:297,

3 Developments in Surgical Management of Breast Cancer 1890s-1970s: Radical mastectomy 1970s: (B-04) Radical mastectomy = Total mastectomy (+/- XRT, delayed axillary management) 1980s: (B-06)Total mastectomy = Lumpectomy + XRT s: Sentinel lymphadenectomy 2000s: (ACOSOC Z001) Narrowed indications for axillary lymphadenectomy

4 Heterogeneity of Breast Cancer Stage (size, nodal status) Focal versus multicentric Histology (type, grade proliferative rate) Hormonal status Her 2 overexpression Molecular profile

5 Systemic Treatment based on tumor characteristics Hormonereceptor Positive (60%-70%) HER2 Positive (20%- 25%) Triple- Negative (~15%) Anti-hormonal Therapy Anti-HER2 Therapy Chemo

6 Systemic Treatment based on tumor characteristics Hormonereceptor Positive (60%-70%) Anti-hormonal Therapy Tamoxifen Selective estrogen receptor modulator Pre- or post-menopausal Aromatase inhibitors Block conversion to estrogen Do not completely suppress ovarian function Post menopausal

7 Systemic Treatment based on tumor characteristics Human Epidermal growth factor Receptor 2 Her2 is amplified in 25-30% of breast cancers Trastuzumab (herceptin) = antibody against extracellular domain Pertuzumab = antibody against extracellular domain HER2 Positive (20%-25%) Anti-HER2 Therapy Lapatinib = antibody against intracellular domain

8 Systemic Treatment based on tumor characteristics AC = doxorubicin (anthracycline) + cyclophosphamide TC = docetaxel (taxane) + cyclophosphamide TAC = docetaxel + doxorubicin + cyclophosphamide Triple- Negative (~15%) Trastuzumab based therapies AC + herceptin TCH = docetaxel, carboplatin, herceptin Chemo

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10 Oncotype Dx Microarray used to describe tumor s genetic phenotype 21 gene analysis => recurrence score => response to chemotherapy Townsend: Sabiston Textbook of Surgery, 19 th edition.

11 Breast Cancer: Targets on the Horizon Vascular Endothelial Growth Factor inhibitors PolyADP Ribose Polymerase inhibitors PI3 Kinase inhibitors mtor antagonists Histone Deacetylation inhibitors IGFR inhibitors Notch inhibitors Src inhibitors

12 VEGF Inhibition (Bevacizumab) Humanized monoclonal antibody Binds to and neutralizes VEGF Inhibits angiogenesis In combination with chemotherapy, improves progression free survival in metastatic triple negative breast cancer (+3 months) No clear evidence supporting use in neoadjuvant setting Wagner at al. Vascular endothelial growth factor targeted therapies for endocrine refractory or resistant metastatic breast cancer. Cochrane Datatbase of Systemic Reviews 2012 July 11; 7:CD O Shaughnessy et al. Meta-analysis of patients with triple-negative breast cancer from three randomized trials of first-line bevacizumab and chemotherapy treatment for metastatic breast cancer. Cancer Research 2010; 70:452s. vonminckwitz et al. Neoadjuvant chemotherapy and bevacizumab for HER2 negative breast cancer. New England Journal of Medicine 2012; 366: Bear et al. The effect on pcr of bevaciuzumab and/or antimetabolites added to standard neoadjuvant chemotherapy; NSABP protocol B-40. Journal of Clinical Oncology 2011; 29:81s.

13 PARP Inhibition (olaparib, iniparib, veliparib) Poly-A-Ribose Polymerase repairs DNA single strand breaks Target tumor deficiencies in DNA repair? Synergize with DNA damaging therapeutics (chemo, XRT)? Positive results in Phase II trial of iniparib in combination with chemotherapy for metastatic triple negative breast cancer (improved response rate, progression free survival, and overall survival) No difference (in progression free or overall survival) in Phase III trial Glendenning et al. PARP inhibitors: current status and the walk towards early breast cancer. The Breast 2011; 20:S12-9. O Shaughnessy et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. New England Journal of Medicine 2011;364: O-Shaughnessy et al. A randomized phase III study of iniparib in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. Journal of Clinical Oncology 2011; 29 [abstr 1007].

14 PI3K/akt/mTOR Pathway Inhibition Important in tumor proliferation, metabolism, invasion, angiogenesis, cell survival Overactivation in some triple-negative breast cancers McAuliffe et al. Deciphering the role of PI3K/akt/mTOR pathway in breast cancer biology and pathogenesis. Clinical Breast Cancer 2010; 10:S59-65.

15 References Bear et al. The effect on pcr of bevaciuzumab and/or antimetabolites added to standard neoadjuvant chemotherapy; NSABP protocol B-40. Journal of Clinical Oncology 2011; 29:81s. Fisher et al. Comparison of radical mastectomy with alternative treatments for primary breast cancer. Cancer 1977; 39: Fisher et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New England Journal of Medicine 2002; 347(16): Glendenning et al. PARP inhibitors: current status and the walk towards early breast cancer. The Breast 2011; 20:S12-9. Guiliano et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Annals of Surgery 1994; 220(3): Liedtke et al. Breast cancer molcular subtypes Modern therapeutic concepts for targeted therapy of a heterogenous entity. Maturitas 2012; 73(4): McAuliffe et al. Deciphering the role of PI3K/akt/mTOR pathway in breast cancer biology and pathogenesis. Clinical Breast Cancer 2010; 10:S O Shaughnessy et al. Meta-analysis of patients with triple-negative breast cancer from three randomized trials of first-line bevacizumab and chemotherapy treatment for metastatic breast cancer. Cancer Research 2010; 70:452s. O Shaughnessy et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. New England Journal of Medicine 2011;364: O Shaughnessy et al. A randomized phase III study of iniparib in combination with gemcitabine/carboplatin in metastatic triplenegative breast cancer. Journal of Clinical Townsend. Chapter 36: Diseases of the Breast. Sabiston Textbook of Surgery. 19 th edition. vonminckwitz et al. Neoadjuvant chemotherapy and bevacizumab for HER2 negative breast cancer. New England Journal of Medicine 2012; 366: Wagner at al. Vascular endothelial growth factor targeted therapies for endocrine refractory or resistant metastatic breast cancer. Cochrane Datatbase of Systemic Reviews 2012 July 11; 7:CD

16 Thank you Ingrid Meszoely Vanderbilt Breast Center

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18 Surveillance/Treatment is Guided by Risk Profile GAIL Model Clauss Model