Chemotherapeutic Treatment
Options for Triple Negative
Breast Cancer
Lauren Barney
April 17, 2013
Peyton Lab
Breast Cancer Subtypes
• Breast cancer is classified into clinical subtypes
based upon receptor expression
• These subtypes dictate possible therapeutic
options and vary in their prognosis
– Luminal: derived from the luminal cells
• ER+, PR+
• Can use hormonal therapy
• Less aggressive
Luminal A
– Basal: derived from myoepithelial cells
• ER-, PR• No specific target for therapies
• More aggressive
Luminal B
– HER2-enriched
• More aggressive
ER: estrogen receptor
PR: progesterone receptor
HER2: human epidermal growth factor receptor 2
Claudin-Low
Basal
HER2-enriched
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Luminal and Basal Characteristics
Basement membrane
Basal
Luminal
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•
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•
•
•
•
•
•
•
•
•
•
•
Low ER
Low HER2
High CK5/6
c-KIT higher
High EGFR
High p53
mutation
High p53
protein
High cyclin E
Very high
vimentin
•
•
•
High ER
Higher HER2
Low CK5/6
Low c-KIT
Low EGFR
Low p53
mutation
Low p53
protein
Low cyclin E
Low vimentin
Myoepithelial Cells  Basal
Luminal Cells  Luminal
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Triple Negative Breast Cancer
• 15-25% of all breast cancer, but much higher
proportion of all breast cancer mortality
• Lack ER, PR and HER2 – no targeted therapies
• Much more aggressive
– Younger age at diagnosis, high grade, large tumor size,
aggressive relapse
• High proliferation, poor differentiation, basal marker
(cytokeratin 5/6) expression, and aggressive clinical
course, with early relapse and decreased survival
• TN tumors have specific morphologic characteristics:
elevated mitotic count, tumor necrosis, pushing
margin of invasion, and stromal lymphocytic response
and high nuclear-cytoplasmic ratio
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TN vs Basal Subtypes
• The terms triple negative and basal are often used interchangeably
in breast cancer subtyping.
– Triple negative denotes the lack of ER, PR and HER2 receptors (clinical
observation)
– Basal describes the tumors that overexpress those genes that
characterized breast basal epithelial cells based on gene expression
– These often overlap!
• Basal-like breast cancer is characterized
by certain features that include the TN
phenotype, but TN and basal-like are not
synonymous terms. A discordance of up
to 30% has been described between the
two groups.
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Treatments can be targeted for cancers that express hormonal
receptors or HER2; TN remains a clinical challenge.
•
Hormonal therapy: blocks
estrogen activity
– Tamoxifen, ER antagonist
– Competitively binds to ER &
inhibits estrogen effects
•
HER2 targeted therapy
– Herceptin & others
• These targeted therapies
work really well!
•
There is no specific target
on TN cells! Must use
cytotoxic
chemotherapeutics,
surgery, radiation.
Tamoxifen
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Current Options for TNBC
• Standard course of treatment is very
aggressive: surgery with adjuvant and
neoadjuvant chemotherapy and radiation
therapy
– Neoadjuvant: administration of a drug before a
main treatment – increases rate of breast
conserving therapies and helps to understand a
patient’s response to drugs
– Adjuvant: any therapy given after primary
therapy – used when there is a high risk of
recurrence
• The search is on for specific targets!
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TNBC Treatment
• Chemotherapy typically includes combinations of
taxanes (T), anthracyclines (A), and
oxazophorines (C)
– Taxanes: disrupt microtubules & inhibit cell division
• Paclitaxel, docetaxel
– Anthracyclines: most effective chemotherapeutics!
• Three mechanisms: inhibit DNA and RNA synthesis, blocks
transcription and replication, creates oxygen free radicals
• Daunorubicin, doxorubicin, epirubicin, idarubicin
– Oxazophorine: DNA alkylating agent
• Cyclophosphamide (C)
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Taxane and Anthracycline Based
Therapy
• Typical regimens:
– AC-T: doxorubicin plus cyclophosphamide every
2 weeks for four cycles followed by docetaxel
every 2 weeks for 4 cycles
• Investigating taxol before AC (not standard therapy)
– TAC: docetaxel, doxorubicin, and
cyclophosphamide every 3 weeks for 6 cycles
• Different dosing regimens, frequencies can
help to improve efficacy
– Dense dosing is better (more frequent doses are
better)
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CMF therapy may actually reduce
recurrence of TNBC compared to
anthracycline or taxane-based treatment
• CMF is a much older therapeutic regimen than TAC
or AC-T
• Cyclophosphamide (alkylating agent, oxazophorine)
• Methotrexate (antimetabolite, stops cell growth &
division)
• Fluorouracil (called 5FU; pyrimidine analog,
antimetabolite)
• Many different dosing schedules possible
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TN Tumors are Chemosensitive
• Recently, studies have shown that TNBC is more
responsive to anthracycline or
anthracycline/taxane chemotherapy than Luminal
subtypes
– Patients who had a complete response to
chemotherapy had good prognosis regardless of
subtype
• Despite this, TNBC patients still have a worse
distant disease free-survival and a poor prognosis
– Result of high likelihood of relapse in TNBC
• HER2+ subtype has a similar response to TNBC
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Beyond brute force chemo: What are some
potential treatment options for TNBC?
• Current and developing therapies
– Many in clinical trials
– Most target proliferative pathways
• Targets: General proliferation, surface molecules,
secondary messengers
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Potential Systemic Targets for TNBC
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Platinum Agents
• Platinum agents can
bind to DNA and cause
cross-linking to occur
 cell death
• Cisplatin, carboplatin
and oxaplatin are
approved for some
types of cancers and
are being studied as
treatments for TNBC
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PARP Inhibitors
• PARP: poly ADP ribose polymerase
– Involved in DNA repair by detecting singlestrand breaks
– Can be activated in cells with damaged DNA
• Several types of cancer are more
dependent on PARP, so it can be a good
therapeutic target
• PARP inhibitors prevent breaks from being
repaired, causing cell death.
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Anti-EGFR
• EGFR is overexpressed in 45-70% of TNBC
• Cetuximab is an anti-EGFR antibody used to
treat metastatic cancer
– Breast cancer patients with metastatic disease
respond twice as well when Cetuximab is added
• Other treatments include tyrosine kinase
inhibitors (erlotinib, gefitinib)
– Gefitinib is the only one currently approved for
breast cancer, but the others are in clinical trials
• Inhibits an important signaling pathway and
provides a specific target!
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Angiogenesis in Cancer
• Angiogenesis: formation of new blood vessels.
– Tumors need blood vessels to grow and spread.
• Angiogenesis inhibitors prevent the formation of
new blood vessels, thereby stopping or slowing
the growth or spread of tumors.
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Anti-Angiogenesis
• Bevacizumab (Avastin)
– Monoclonal antibody to VEGF
– Improves survival in breast cancer patients with combined with Taxol
– Approved for metastatic breast cancer but benefit isn’t subtype specific
– this has since been revoked because it slowed progression but didn’t
extend length or quality of life and had many adverse effects
• Metronomic chemotherapy: repeated, low, less than toxic doses
can destroy endothelial cells and prevent angiogenesis, slowing
tumor growth – works in clinical trials
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Androgen Receptor
• Nuclear receptor activated by binding testosterone or
dihydrotestosterone
– Closely related to PR
• Expressed in 75% of breast cancer and 10-20% of
TNBC
– TNBC that express AR are molecularly similar to prostate
cancer and could potentially be treated similarly.
• Bicalutamine: anti-androgen used to treat prostate
cancer
• 17-DMAG: semi-synthetic antibiotic derivative, has
shown promise in clinical trials
• Enzalutamide: androgen agonist used to treat prostate
cancer; is in Phase II for TNBC
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RTK Inhibitors
• Suninitib (Sutent)
– Multiple-target RTK inhibitor
• All PDGFRs and VEGFRs
• KIT (CD17) which drives the majority of all GI stromal
tumors & several others
• Imatinib (Gleevec)
– Prevents phosphorolation of BCR-Abl, inhibiting
signaling pathways necessary for cancer cell
growth
• BCR-Abl: Exists only in cancer cells!
• Worked in vitro; no effect on metastatic breast cancer
patients in Phase II
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Src Tyrosine Kinase
• Src is overexpressed in breast cancer
• Dasatinib: multiple tyrosine kinase inhibitor
approved for CML
– Possible efficacy in breast cancer - small
effect seen in Phase II
– In vitro: basal breast cancer cells were more
sensitive!
• Several others in trials also seem to have
promising preclinical activity
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mTOR
• Cell cycle regulator and a downstream effector in
the PI3K/PTEN/AKT pathway
• PTEN is often mutated in TNBC, leading to
increased AKT and mTOR activation
• Everolimus and temsirolimus block mTOR function
and inhibit proliferation
– Everolimus is approved for some types of cancers currently in clinical trials for TNBC in combination with
chemotherapy
– Temsirolimus is approved for renal cell carcinoma and
completed a Phase II trial with promising results
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Other possible therapeutic options
• Hsp90 (heat shock protein 90) – upregulated
in response to stress signals; regulates and
stabilizes many key proteins, including
downstream targets of p53, PI3K, AKT and
EGFR – can be recruited to ‘protect’
oncogenic proteins, leading to protein
overexpression
• HDAC (Histone deacetylase) – can effect
epigenetics and cause re-expression of
epigenetically silenced genes
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Other ways to sensitize cells to
chemotherapy
• Inhibition of TGF-beta sensitizes to chemo
• TRAIL: Lexatumumab (monoclonal
antibody in clinical trials)
– TRAIL controls proliferation & induces
apoptosis
• Chk1 (checkpoint kinase 1): involved in
cell cycle control.
– Inhibition sensitizes proliferating tumor cells to
chemotherapies that damage DNA
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Mutations that Could be Targeted
• p53 (75% of TNBC) – complex, so target
downstream components of pathway
• Myc (40% of TNBC)
• Loss of retinoblastoma gene (20% of TNBC)
• Mutation in BRCA1 or BCRA2 (15-20% of TNBC)
• Rare:
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–
–
–
PTEN
PIK3CA
Amplification of HER2
Amplification of FGFR2
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We need to get creative: changes
in formulation
• EndoTAG®-1: formulation of paclitaxel combined with neutral and
positive lipids
– Interacts with newly developing and negatively charged endothelial cells
that are forming new blood vessels
– Attacks the activated endothelial cells as they divide
– Targets blood supply to tumors without affecting healthy tissue
– Prevents angiogenesis and inhibits tumor growth!!
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What’s in clinical trials now?
• New compounds
• New drug combinations or dosing regimens
• New formulations
Interesting Current Clinical Trials
• Re-expression of ER in Triple Negative Breast Cancers
• Bevacizumab, Metronomic Chemotherapy (CM), Diet and
Exercise After Preoperative Chemotherapy for Breast Cancer
• Laboratory-Treated T Cells After Chemotherapy in Treating
Women With Stage II or Stage III Breast Cancer Undergoing
Surgery
• Preoperative Clinical Trial of Sorafenib in Combination With
Cisplatin Followed by Paclitaxel for Triple Negative (ER-, PR-,
Her2-) Early Stage Breast Cancer
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Recent news stories
• March 18, 2013 - Copper depletion shows
early success in triple-negative breast cancer
• April 8, 2013 – Paragazole (HDAC) excels in
preclinical models of triple-negative breast
cancer
• April 12, 2013 - Omega-3 Fatty Acids Slow
Triple-Negative Breast Cancer Cell
Proliferation
• April 15, 2013 - Nanodiamonds could
improve effectiveness of breast cancer
treatment
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Outlook for now and future
• Need targeted therapies, new formulations
to be able to treat TNBC
– Combination therapies will be necessary
because tumors are heterogeneous and can
change
– Also need to attack tumors from all sides
– Reaching complete remission and preventing
recurrence are key
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References
• A. Bosch et al. Cancer Treatment Reviews 36 (2010) 206–215
• Cleator et al. Triple-negative breast cancer: therapeutic options.
Lancet Oncol 2007; 8: 235–44
• Pal et al. Triple negative breast cancer: unmet medical needs.
Breast Cancer Res Treat (2011) 125:627–636
• Crown et al. Emerging targeted therapies in triple-negative breast
cancer. Annals of Oncology 23 (Supplement 6): vi56–vi65, 2012
• Oncology (Williston Park). 2008 October ; 22(11): 1233–1243.
• Hudis and Gianni. Triple-Negative Breast Cancer: An Unmet Medical
Need. The Oncologist 2011, 16:1-11. doi:
10.1634/theoncologist.2011-S1-01
• Lisa A. Carey, E. Claire Dees, Lynda Sawyer, et al. Clin Cancer Res
2007;13:2329-2334.
• Turner N et al. Targeting triple negative breast cancer: Is p53 the
answer? Cancer Treat Rev (2013), http://dx.doi.org/
10.1016/j.ctrv.2012.12.001