Diagnosis and Treatment of Breast Cancer: A Core Lecture

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• 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
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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

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Epidemiology of breast cancer

• Female/male ratio 1001
• More than 200,000 women will be Dxd in US in 2013
• gt40,000 will die of breast cancer in 2013
• 2nd leading cause of cancer deaths in women

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Breast cancer death rate is declining
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Staging of Breast Cancer I
II III III-IBC
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Stage Four Breast Cancer

• Distant Metastasis

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Types of Breast Cancer

• Ductal (2/3 of all breast cancers)
• Lobular (1/3 of all breast cancers)

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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

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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

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Estrogen, Estrogen Receptor and Anti-estrogens
Aromatase Inhibitors (AIs) Anastrozole Selecti
ve Estrogen Receptor Modulators (SERMs)
Tamoxifen Selective Estrogen Receptor
Downregulators (SERDs) Fulvestrant AI and
SERD Anastrozole and Fulvestrant
Courtesy NCI
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HER2 Over-Expression (IHC3 or FISH) and
Anti-HER2 in Breast Cancer Monoclonal
Antibodies Trastuzumab and Pertuzumab Tyrosine
Kinase Inhibitor Lapatinib Neratinib
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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)

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Chemotherapy and Targeted Rx

• Ado Trastuzumab Emtansine (chemotherapy
  molecule) attached via a linker molecule to
  Trastuzumab (monoclonal antibody).

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KaplanMeier 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!
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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.

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CLEOPATRA Progression-free Survival, as Assessed
at an Independent Review Facility.
It also improved OS!
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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)435-444 August 2, 2012
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S0226 Schema
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011
R A N D O M I Z E
This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
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20 PFS Benefit
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19 OS Benefit
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Treatment of Early Breast Cancer (Stage I-III)
Chemotherapy
Chemotherapy
Microscopic cancer cells
Surgery
Breast cancer
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
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Preoperative Chemotherapy Trastuzumab
Young adult with HER2-pos. primary Resistant IBC
(2003)
Preoperative Chemotherapy
Eureka! Dec 2003Letter 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.
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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
  (n1872) compared with the group that received
  chemotherapy alone (n1880)
• 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 (n1074) compared with the group
  that received chemotherapy alone (n1073)

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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) 3286-8
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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
358197-199January 10, 2008 JCO 2009 JNCI 2008
Now a standard preferable first line Rx per NCCN
And PDQ guidelines
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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?
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FDA allowed pathologic complete response
endpoint for accelerated approval of Pertuzumab
2013. A Decade Long Odyssey 2003-2013 comes to an
end.
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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

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Pearls

• 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

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What Did We Learn

• Epidemiology gt200,000 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
  

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Thank You

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