1. Diagnosis and Treatment of Breast Cancer: A Core Lecture
Rita Mehta, MD
Health Science Clinical Professor
Div. of Hem/Oncology
School of Medicine
Medical Director of Breast Cancer Center
October 2014

2. What Will We Learn Epidemiology of Breast Cancer
Stages of Breast Cancer
Morphologic Sub-types of Breast cancer
IHC Sub-types of Breast Cancer
Treatment of metastatic Breast Cancer
Pre/Postoperative treatments of Breast Cancer 2

3. Epidemiology of breast cancer
Female/male ratio 100:1
More than 200,000 women will be Dxd in US in 2013
>40,000 will die of breast cancer in 2013
2nd leading cause of cancer deaths in women

4. Breast cancer death rate is declining

5. Staging of Breast
Cancer
I II
III III-IBC

6. Stage Four Breast Cancer
Distant Metastasis

7. Types of Breast Cancer Ductal (2/3 of all breast cancers)
Lobular (1/3 of all breast cancers)

8. Systemic Chemotherapy
Anthracyclines (Doxorubicin) Alkylators (Cyclophosphamide) Antimetabolites (Methotrexate) Taxanes (Paclitaxel, docetaxel) And Platinums Optimal Chemotherapy Scheduling (dose-dense or metronomic (weekly) paclitaxel. Bisphosphonates? A meta-analysis shows benefit restricted to postmenopausal women

9. Targeted Treatment
Era Of Targeted Treatment began 100 years ago with oopherectomy, and then the target was found.
2000: Trastuzumab followed the discovery of the target HER2

10. Estrogen, Estrogen Receptor and Anti-estrogens:
Aromatase Inhibitors (AIs): Anastrozole
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant
AI and SERD:
Anastrozole and Fulvestrant
Courtesy NCI 10

11. HER2 Over-Expression (IHC3+ or FISH+) and Anti-HER2 in Breast Cancer
Monoclonal Antibodies:
Trastuzumab
and
Pertuzumab
Tyrosine Kinase Inhibitor:
Lapatinib
Neratinib 11

12. Four Subtypes of Breast Cancer
HR-negative and HER2-negative (Triple Negative)
HR-negative and HER2-positive (HER2-enriched)
HR-positive and HER2-negative (HR-positive)
HR-positive and HER2-positive (Triple positive)

13. Chemotherapy and Targeted Rx
Ado Trastuzumab: Emtansine (chemotherapy molecule) attached via a linker molecule to Trastuzumab (monoclonal antibody).

14. Kaplan–Meier Estimates of Progression-free Survival, According to Whether Patients Were Randomly Assigned to Receive Chemotherapy plus Trastuzumab or Chemotherapy Alone (Panel A), and Whether Chemotherapy Consisted of Either a Combination of an Anthracycline and Cyclophosphamide (Panel B) or Paclitaxel (Panel C).
It also improved OS!
Slamon DJ et al. N Engl J Med 2001;344:

15. CLEOPATRA: The Study Overview
Pertuzumab, an anti-HER2 antibody, recognizes a different epitope of HER2 than does trastuzumab and behaves differently.
In patients with metastatic breast cancer, the combination of the two antibodies plus docetaxel (NCCN allows paclitaxel substitution) significantly increased progression-free and Overall Survival.

16. CLEOPATRA: Progression-free Survival, as Assessed at an Independent Review Facility.
It also improved OS!
Baselga J et al. N Engl J Med 2012;366:

17. Original Article Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer
Rita S. Mehta, M.D., William E. Barlow, Ph.D., Kathy S. Albain, M.D., Ted A. Vandenberg, M.D., Shaker R. Dakhil, M.D., Nagendra R. Tirumali, M.D., Danika L. Lew, M.A., Daniel F. Hayes, M.D., Julie R. Gralow, M.D., Robert B. Livingston, M.D., and Gabriel N. Hortobagyi, M.D.
N Engl J Med
Volume 367(5):
August 2, 2012 17

18. S0226: Schema Arm 1 R Anastrozole A N D O M I Z E Arm 2 Anastrozole
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011
S0226: Schema R A N D O M I Z E
Arm 1
Anastrozole
Arm 2
Anastrozole
Fulvestrant
This presentation is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute.

19. 20% PFS Benefit

20. 19% OS Benefit

21. Treatment of Early Breast Cancer (Stage I-III)
Chemotherapy
Chemotherapy
Breast cancer
Microscopic cancer cells
Surgery
Cancer free
Early response leads to high complete response at surgery.
Complete response (pathologic specifically) predicts more than 90% long-term survival for the patient
Group-Specific high complete response predicts group-specific survival outcomes

22. Preoperative Chemotherapy +Trastuzumab
Young adult with HER2-pos. primary Resistant IBC (2003)
Eureka! Dec 2003:Letter to NSABP: 5/5 pCR: Historical control 2%: “Trastuzumab should be standard Rx”
Reply: FDA will not give approval based on pCR!
Patient with HER2-positive IBC Relapsed after postoperative chemotherapy (2003)
Pre Rx
Mid Rx
Post Rx
pCR
pCR
Annals of Oncology: Trastuzumab in inflammatory breast cancer; Mehta et al. 2008; pCR: pathologic complete response. The patient is the teacher of a clinician. 22

23. Preoperative Rx predicted benefit of Postoperative Rx
Breaking News
Studies 1 & 2: [NSABP 31 (UCI) and NCCTG] NEJM Oct 2005
52% higher chance of remaining cancer free longer in the group of women who received Herceptin* (n=1872) compared with the group that received chemotherapy alone (n=1880)
Study 3/4: Slamon et al. NEJM 2012
40% higher chance of remaining cancer free longer in the group of women who received Standard AC and Herceptin * (n=1074) compared with the group that received chemotherapy alone (n=1073)

24. HER2/HR negative (Triple Negative) breast cancer
Preoperative Dose-Dense/Metronomic/Carboplatin predicted benefit of Postoperative Rx
HER2/HR negative (Triple Negative) breast cancer
A young patient with stage III cancer (FHx negative, BRCA negative)
Achieves pathologic complete response following accelerated chemotherapy, and carboplatin.
Now a standard preferred first line Rx per NCCN 2013 and PDQ guidelines 2012
20% (non-DD)-70% (DD) patients achieve pathologic complete response
Fast forward 2014:
Dose dense chemoRx and Carboplatin should be considered in Rx of TN breast cancer (50% pCR)
Agrawaal et al. J Clin Oncol December 2007;
Mehta RS: J Clin Oncol 2008; 26 (19):

25. HER2-negative, hormone receptor-pos IBC
Preoperative (DD AC followed by Metronomic paclitaxel based regimen) Weekly Chemotherapy
Mehta RS; HER2 and Response to Paclitaxel in Node-Positive Breast Cancer
N ENGL J MED 2008; 358: January 10, 2008; JCO 2009; JNCI 2008
Now a standard preferable first line Rx per NCCN And PDQ guidelines

26. What are the challenges?
Pre Rx
Mid Rx
Post Rx
Up-to 20-50% patients may not achieve subtype-specific complete response. A resistant disease is a resistant disease?

27. FDA allowed pathologic complete response endpoint for accelerated approval of Pertuzumab 2013.
A Decade Long Odyssey comes to an end.

28. Treatment of Stage I-III Breast N Cancer
Chemotherapy (4-6 months) Pre or Post Surgery (Lumpec-/Mastectomy with LND)
+Trastuzumab/Pertuzumab (6-12 months) if HER2+, Pre (or Post) Surgery
Radiation Rx: Generally post surgery
Hormonal Modulating Agents up to 10 years if HR+: Generally post Surgery

29. Pearls Survival is 4+ years for HER+ Metastatic BC
Test the target (HR and HER2) and treat.
Prolonged HER2 suppression is important in HER2-positive MBC(with chemotherapy) but not curative setting.
Prolonged Hormonal blockade is important in curative setting, and in MBC (with chemotherapy)?
While treatment intent in early BC is curative that in metastatic BC is palliative.
Survival is about 2 years for HR- and 4 years for HR+ Metastatic BC
Survival is 4+ years for HER+ Metastatic BC

30. What Did We Learn
Epidemiology: >200,000 BC/year incidence, and falling BC death rates
Morphologic types of breast cancer: IDC and ILC
Stages of breast bancer: Stages I-IV
IHC Sub-types of breast bancer: 4
Treatment of metastatic breast cancer: ChemoRx Sequential (or Combination if visceral crisis), Hormonal Rx (Combination or Sequential?) and HER2-Targeted Rx (Combination chemo and HER2 targeted Rx and Maintenance)
Preoperative/Postoperative treatment of Breast Cancer: ChemoRx, Hormonal Rx and HER2-Targeted Rx

31. Thank You
Patients who made this presentation possible, and thank you for participating in this mutual learning process !