Transcript Understanding and Treating Triple

Understanding and
Treating Triple-Negative
Breast Cancer
Elshami M. Elamin, MD
Medical Oncologist
Central Care Cancer Center
www.cccancer.com
Wichita, KS - USA
Molecular Subtypes of Breast Cancer
1. Luminal A: ER+ and or PR+ Her2 -ve
2. Luminal B: ER+ and or PR + Her2+
3. Her2: Her2+ ER-ve PR-ve
4. Basal-like: ER-ve PR-ve Her2-ve,
cytokeratin 5/6+, and or Her1+
5. Normal-like: negative for all markers
Basal-like tumors
Mostly ER/HER2–negative
Marked increases in mitotic count,
geographic necrosis
Pushing borders of invasion
Stromal lymphocytic response
BRCA1, BRAC2 Mutation Carrier
BRCA1:
Chromosome 17
57% risk of breast, 40% ov ca
Bil breast ca
ER-PR –ve
Higher G
Basal-like
BRCA 2:
Chromosome 13
49% risk of breast, 18% ov ca
Pancreatic, prost, bile/GB, stomach
ER/PR +ve
BRCA 1-2:
2/3 - 3/5 of familial breast ca
50-87% risk of invasive breast ca
15- 65% risk of invasive epith ovarian ca
Epidemiology
In 2008, it is estimated that over 1 million
women worldwide will be diagnosed with
breast cancer, of which 172,695 will be
classified as “triple-negative.
TNBC
ER/PR/Her2-neu negative
It is characterized by:
unique molecular profile
majority carry the “basal-like” molecular profile on gene
expression arrays
majority of BRCA1-associated breast cancers are TN and
basal-like
the extent to which the BRCA1 pathway contributes to the
behavior of sporadic basal-like breast cancers is an area of
active research
aggressive behavior
younger age
higher mean tumor size
higher-G
higher rate of node positivity
distinct patterns of metastasis
Early relapse
Predilection for visceral metastasis, including brain
lack of targeted therapies
TNBC
Increasing evidence suggests that the risk
factor profile differs between this subtype
and the more common luminal subtypes.
TNBC
Although sensitive to chemotherapy, early
relapse is common
Targeted agents, (EGFR, VEGF, PARP)
inhibitors, are currently in clinical trials and
hold promise in the treatment of this
aggressive disease
Relationship between TNBC, BRCA
and Basal-like phenotype
Triple-negative is a term based on clinical
assays for ER, PR, and HER2
Basal-like is a molecular phenotype initially
defined using cDNA microarrays
characterized by low expression of ER, PR, and HER2
Not all TNBC are basal-like
Majority of BRCA1-associated breast cancers
are triple-negative and express a high proportion
of basal-like cytokeratins
Current Treatment for Metastatic TNBC
No FDA-approved
treatment option specifically
for metastatic TNBC
Limited treatment options
for metastatic TNBC
– Most patients already
treated with adjuvant
anthracycline, taxane, and
cyclophosphamide
– PFS ≤ 4 mos with
chemotherapy for
metastatic disease
Rationale for gemcitabine/
carboplatin in MBC
– Synergistic antitumor activity
between gemcitabine and
carboplatin
– Active combination in MBC,
with response rates from
21% to 53%
Rationale for PARP inhibitor–
based therapy in TNBC
– PARP1 is upregulated in
majority of triple-negative
human breast cancers
1. Kassam F, et al. Clin Breast Cancer. 2009;9:29-33.
2. Li HC, et al. Oncology (Williston Park). 2004;18(14 suppl 12):17-22.
3. Loesch D, et al. Clin Breast Cancer. 2008;8:178-188.
Anthracycline/Taxane–Based
Chemotherapy
Two neoadjuvant studies:
proportionally higher sensitivity to anthracycline- or
anthracycline/taxane–based chemo for basal-like/ERnegative breast cancers compared to luminal/ER-positive
subtypes
Despite initial chemosensitivity, DFS (P = .04) and OS
(P = .02) remained poorest among those with basal-like and
HER2-positive tumors compared to luminal tumors
Pts with a pCR had excellent outcomes regardless of
subtype
the poorer outcome among triple-negative patients was
attributed to a higher rate of recurrence among patients
with residual disease
Platinum
Tumors with BRCA1 dysfunction harboring
deficient double-stranded DNA break repair
mechanisms are sensitive to agents that cause
DNA damage, such as platinum agents*
*Garber J, Richardson A, Harris L, et al: Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC) (abstract 3074). Breast
Cancer Res Treat 100(suppl 1), 2006.
*Sirohi B, Arnedos M, Popat S, et al: Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol June 20, 2008 (epub
ahead of print).
*Yi S, Uhm J, Cho E, et al: Clinical outcomes of metastatic breast cancer patients with triple-negative phenotype who received platinumcontaining chemotherapy (abstract 1008). J Clin Oncol 26(15S):43s, 2008.
Targeted Strategies
EGFR expression is seen in approximately
60% of TNBC
phase II trial (cetuximab + carbo):
18% RR, 27%% overall clinical benefit rate
CPT11/carbo +/- cetuximab
49% vs 30% RR
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