Transcript Diagnosis and Treatment of Breast Cancer

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
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
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

Breast cancer death rate is declining
Staging of Breast
Cancer
I
III
II
III-IBC
Stage Four Breast Cancer

Distant Metastasis
Types of Breast Cancer
Ductal (2/3 of all breast cancers)
Lobular (1/3 of all breast cancers)
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
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

Estrogen, Estrogen
Receptor and Antiestrogens:
Aromatase Inhibitors (AIs):
Anastrozole
Selective Estrogen Receptor
Modulators (SERMs):
Tamoxifen
Selective Estrogen Receptor
Downregulators (SERDs):
Fulvestrant
AI and SERD:
Anastrozole and Fulvestrant
Courtesy NCI
HER2 OverExpression (IHC3+
or FISH+) and
Anti-HER2 in
Breast Cancer
Monoclonal
Antibodies:
Trastuzumab
and
Pertuzumab
Tyrosine Kinase
Inhibitor:
Lapatinib
Neratinib
Four Subtypes of Breast Cancer
• HR-negative and HER2-negative (Triple
Negative)
• HR-negative and HER2-positive (HER2enriched)
• HR-positive and HER2-negative (HRpositive)
• HR-positive and HER2-positive (Triple
positive)
Chemotherapy and Targeted Rx
• Ado Trastuzumab: Emtansine
(chemotherapy molecule) attached via a
linker molecule to Trastuzumab
(monoclonal antibody).
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;344:783-792.
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.
CLEOPATRA: Progression-free Survival, as
Assessed at an Independent Review Facility.
It also improved
OS!
Baselga J et al. N Engl J Med 2012;366:109119
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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011
S0226: Schema
Arm 1
R
A
N
D
O
M
I
Z
E
Anastrozole
Arm 2
Anastrozole
Fulvestrant
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Kaplan–Meier Curves for Progression-free Survival, According to Treatment Group.
20% PFS Benefit
Mehta RS et al. N Engl J Med 2012;367:435-444
Kaplan–Meier Curves for Overall Survival, According to Treatment Group.
19% OS Benefit
Mehta RS et al. N Engl J Med 2012;367:435-444
Treatment of Early Breast Cancer
(Stage I-III)
Chemotherapy
Chemotherapy
Microscopic
Surgery
Breast
Cancer free
cancer cells
cancer
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
Preoperative Chemotherapy +Trastuzumab
Young adult with HER2pos. primary Resistant
IBC (2003)
Preoperative Chemotherapy
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.
Eureka! Dec
2003:Letter
to NSABP:
5/5 pCR:
Historical
control 2%:
“Trastuzuma
b should be
standard Rx”
Reply: FDA
will not give
approval
based on
pCR!
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)
Preoperative Dose-Dense/Metronomic/Carboplatin
predicted benefit of Postoperative Rx
A young patient with stage
HER2/HR negative (Triple Negative) breast cancer 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:
Agrawaal et al. J Clin Oncol December 2007;
Mehta RS: J Clin Oncol 2008; 26 (19): 3286-8
Dose dense chemoRx and
Carboplatin should be
considered in Rx of TN
breast cancer (50% pCR)
HER2-negative, hormone receptor-pos IBC
Preoperative (DD AC followed by Metronomic paclitaxel
based regimen) Weekly Chemotherapy
Now a standard
preferable first line Rx per
NCCN And PDQ
guidelines
Mehta RS; HER2 and Response to Paclitaxel
in Node-Positive Breast Cancer
N ENGL J MED 2008; 358:197-199January 10,
2008; JCO 2009; JNCI 2008
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?
FDA allowed pathologic
complete response endpoint
for accelerated approval of
Pertuzumab 2013.
A Decade Long Odyssey 20032013 comes to an end.
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

Pearls
• Test the target (HR and HER2) and treat.
• Prolonged HER2 suppression is important in HER2positive 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
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

Thank You
Patients who made this presentation
possible, and thank you for
participating in this mutual learning
process !