Targeted therapies for Early Stage Breast Cancer. Cynthia Vakhariya D.O. Providence Hospital

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1 Targeted therapies for Early Stage Breast Cancer Cynthia Vakhariya D.O. Providence Hospital

2 Case 55-year-old postmenopausal woman Routine screening mammogram 3 cm irreg mass in L breast Left breast ultrasound Multiple masses in the left breast Largest measures 3 x 2.7 x 2.5 cm Axillary lymph nodes enlarged

3 Case Left breast biopsy of largest mass and axillary lymph node Invasive moderately to poorly differentiated ductal carcinoma Grade 3 ER+/PR+ Her 2 neu 2+ FISH +

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5 Risk Prediction for Adjuvant Therapy Lymph node status (extent & #) Tumor histology Tumor Size Grade ER/PR status up to 65-75% of cases Her 2 neu status 20% of cases Triple negative 15%

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7 Background Henri Francois Le Dran ( ) Hypothesis that breast cancer spread in an orderly fashion Halstedian theory Local and regional nodes were the first site of metastatic spread Effective barriers against further spread Systemic therapy is believed to be effective

8 Rationale for Hormone therapy Thomas Beatson (1896) reported first series of surgical oophorectomy Tumor regression by castration Prevent breast cancer cells from receiving stimulation from endogenous estrogen Regression of cutaneous metastasis

9 History and Evolution 1941 Dr Charles Higgins First discovery of hormonal treatment of cancer Nobel prize lecture on 12/13/66 Described 8 cancers which were hormone responsive

10 Estrogen Production in Premenopausal and Postmenopausal Patients

11 Mechanism of action All endocrine therapies target the estrogen receptor at one level or another While the PR receptor does not act as a target directly, it is an ER induced gene SERM Tamoxifen Aromatase Inhibitors Exemastine, Anastrozole, Letrozole

12 Chronology of Endocrine Therapy Oophorectomy for advanced disease 1944 Estrogen for advanced disease Tamoxifen for advanced disease 1970s Importance of steroid receptors 1980s Adjuvant tamoxifen LHRH analogs for advanced disease 1990s Tamoxifen for risk reduction Aromatase inhibitors for advanced disease Development of other SERMS 2000s Adjuvant aromatase inhibitors Adjuvant LHRH agonists +/- tam or AI

13 History and Evolution

14 EBCTCG:Tamoxifen vs Placebo

15 Aromatase Inhibitors: Mechanism of Action

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17 Adjuvant Trials of Aromatase Adjuvant Trials of Aromatase Inhibitors: Substitute or in Inhibitors Sequence with Tamoxifen MA17 NSABP-B-33 BIG FEMTA ARNO ITA GROCTA 4B Tamoxifen Anastrozole Letrozole Exemestane Placebo Aminoglutethimide COOMBES Five years

18 Adverse Events

19 Side Effects Tamoxifen Cataracts Annual eye exam Endometrial CA Annual pap/pelvic VTE/CVA/CAD Hot flashes Mood disorder Interacts with SSRIs Check drug interaction Aromatase Inhibitors Osteoporosis Calcium and Vitamin D supplementation DEXA scan every 2 years Bisphosphonates if bone density loss

20 ATLAS trial Extended Tamoxifen 5 vs 10 years

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22 ? Chemotherapy Not every woman needs chemotherapy Several evidence based choices now available AI x 5 years (ATAC) Tamoxifen x 5-10 years (ATLAS,aTTOM) Tamoxifen x 5 year to AI x 5 year (MA-17) OFS + Tamoxifen (SOFT, E3193) OFS + AI (SOFT/TEXT) Endocrine therapy alone x 5-10 years sufficient for low risk women

23 Prognostic and Predictive Gene Assays Better selection of patients for treatment with chemotherapy Treat only those patients that are most likely to recur AND who will therefore benefit most from the addition of chemotherapy Take advantage of genomics

24 Adjuvant Online

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26 Options for Adjuvant Therapy

27 Adjuvant Therapy Assessing Risk- mortality at 10 years Breast cancer relapse and mortality Tumor size, grade, node groupings, ER Assess benefit from hormonal and chemorx Limitations Size 1.1-2, 2.1-3, etc LNS 1-3, 4-9, > 9 ER positive,negative No her 2 neu

28 Oncotype DX for patients with ER + LN- disease

29 Recurrence Score as a Continuous Predictor Distant Recurrence at 10 Years 40% 35% 30% 25% 20% 15% 10% 5% Low Risk Group Intermediate Risk Group My RS is 30, What is the chance of recurrence within 10 yrs? 95% CI High Risk Group 0% Recurrence Score

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33 Targeted therapies Hormonal therapy was first targeted therapy for breast cancer Monoclonal antibodies Trastuzumab (herceptin)

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42 Triple negative breast cancer Defined as negative for estrogen, progesterone, and Her 2 receptors 15% of all breast cancers More likely younger women ( < 40 years old) or in African american or Hispanic women May be associated with inherited mutation in BRCA 1/2 genes

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44 Immune Therapy

45 Immune therapy

46 Immune therapy Approved in melanoma, lung, renal cell CA Triple negative breast cancers Highest rate of PD-L1 expression Highest rate of mutations High level of immune cells in the tumor cells

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48 Case 55-year-old woman has screening 3D mammogram 8/2015 compared to 12/2013. It shows an asymmetry in the left breast. Left breast ultrasound Multiple masses in the left breast Largest measures 3 x 2.7 x 2.5 cm Axillary lymph nodes enlarged

49 Case Left breast biopsy of largest mass and axillary lymph node Invasive moderately to poorly differentiated ductal carcinoma Grade 3 ER+/PR+ Her 2 neu 2+/FISH +

50 Treatment plan Neoadjuvant chemotherapy Herceptin/Pertuzumab with chemotherapy (Cleopatra Trial) Surgery Radiation Adjuvant endocrine therapy Aromatase Inhibitor (ATAC trial) a goal for 10 years (ATLAS trial)

51 Potential Targets in Breast Cancer

52 Era of Predictive Pathology

53 Conclusions We now live in an era where personalized medicine is not only feasible but expected for breast cancer This is quickly beyond ER/PR and Her-2 and into other molecularly based targets Major problems: Drug resistance Brain metastases Treatment related toxicities Cost of therapy