Chemotherapeutic Treatment Options for Triple Negative Breast Cancer

Lauren BarneyApril 17, 2013

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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

– Basal: derived from myoepithelial cells• ER-, PR-• No specific target for therapies• More aggressive

– HER2-enriched• More aggressive

Luminal A

Luminal B

Claudin-Low

HER2-enrichedBasal

ER: estrogen receptorPR: progesterone receptorHER2: human epidermal growth factor receptor 2

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Luminal and Basal Characteristics

Basal• Low ER• Low HER2• High CK5/6• c-KIT higher• High EGFR• High p53

mutation• High p53

protein• High cyclin E• Very high

vimentin

Basement membrane

Myoepithelial Cells Basal

Luminal Cells Luminal

Luminal• High ER• Higher HER2• Low CK5/6• Low c-KIT• Low EGFR• Low p53

mutation• Low p53

protein• Low cyclin E• Low vimentin

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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 single-

strand 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:

– 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