Chemotherapeutic Treatment Options for Triple Negative Brea - PowerPoint Presentation

Slide1

Chemotherapeutic Treatment Options for Triple Negative Breast Cancer

Lauren Barney

April 17, 2013Slide2

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 cellsER+, PR+Can use hormonal therapyLess aggressiveBasal: derived from myoepithelial cellsER-, PR-No specific target for therapiesMore aggressiveHER2-enrichedMore aggressive

Luminal A

Luminal B

Claudin

-Low

HER2-enriched

Basal

ER: estrogen receptor

PR: progesterone receptor

HER2: human epidermal growth factor receptor 2Slide3

Luminal and Basal Characteristics

Basal

Low ER

Low HER2High CK5/6c-KIT higherHigh EGFRHigh p53 mutationHigh p53 proteinHigh cyclin EVery 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

vimentinSlide4

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 aggressiveYounger age at diagnosis, high grade, large tumor size, aggressive relapseHigh 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 ratioSlide5

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 expressionThese 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. Slide6

Treatments can be targeted for cancers that express hormonal receptors or HER2; TN remains a clinical challenge.

Hormonal therapy: blocks estrogen activity

Tamoxifen

, ER antagonistCompetitively binds to ER & inhibits estrogen effectsHER2 targeted therapyHerceptin & othersThese targeted therapies work really well!There is no specific target on TN cells! Must use cytotoxic chemotherapeutics, surgery, radiation.

TamoxifenSlide7

Current Options for TNBC

Standard course of treatment is very aggressive: surgery with adjuvant and

neoadjuvant

chemotherapy and radiation therapyNeoadjuvant: administration of a drug before a main treatment – increases rate of breast conserving therapies and helps to understand a patient’s response to drugsAdjuvant: any therapy given after primary therapy – used when there is a high risk of recurrenceThe search is on for specific targets!Slide8

TNBC Treatment

Chemotherapy typically includes combinations of

taxanes

(T), anthracyclines (A), and oxazophorines (C)Taxanes: disrupt microtubules & inhibit cell divisionPaclitaxel, docetaxelAnthracyclines: most effective chemotherapeutics!Three mechanisms: inhibit DNA and RNA synthesis, blocks transcription and replication, creates oxygen free radicalsDaunorubicin, doxorubicin, epirubicin

, idarubicin

Oxazophorine: DNA alkylating agentCyclophosphamide (C)Slide9

Taxane

and

Anthracycline

Based TherapyTypical regimens:AC-T: doxorubicin plus cyclophosphamide every 2 weeks for four cycles followed by docetaxel every 2 weeks for 4 cyclesInvestigating taxol before AC (not standard therapy)TAC: docetaxel, doxorubicin, and cyclophosphamide every 3 weeks for 6 cyclesDifferent dosing regimens, frequencies can help to improve efficacyDense dosing is better (more frequent doses are better)Slide10

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-TCyclophosphamide (alkylating agent, oxazophorine)Methotrexate (antimetabolite, stops cell growth & division)Fluorouracil (called 5FU; pyrimidine analog, antimetabolite)Many different dosing schedules possibleSlide11

TN Tumors are Chemosensitive

Recently, studies have shown that TNBC is more responsive to

anthracycline

or anthracycline/taxane chemotherapy than Luminal subtypesPatients who had a complete response to chemotherapy had good prognosis regardless of subtypeDespite this, TNBC patients still have a worse distant disease free-survival and a poor prognosisResult of high likelihood of relapse in TNBCHER2+ subtype has a similar response to TNBCSlide12

Beyond brute f

orce

c

hemo: What are some potential treatment options for TNBC?Current and developing therapiesMany in clinical trialsMost target proliferative pathwaysTargets: General proliferation, surface molecules, secondary messengersSlide13

Potential Systemic Targets for TNBCSlide14

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 TNBCSlide15

PARP Inhibitors

PARP: poly ADP ribose polymerase

Involved in DNA repair by detecting single-strand breaks

Can be activated in cells with damaged DNASeveral types of cancer are more dependent on PARP, so it can be a good therapeutic targetPARP inhibitors prevent breaks from being repaired, causing cell death. Slide16

Anti-EGFR

EGFR is overexpressed in 45-70% of TNBC

Cetuximab

is an anti-EGFR antibody used to treat metastatic cancerBreast cancer patients with metastatic disease respond twice as well when Cetuximab is addedOther treatments include tyrosine kinase inhibitors (erlotinib, gefitinib)Gefitinib is the only one currently approved for breast cancer, but the others are in clinical trialsInhibits an important signaling pathway and provides a specific target!Slide17

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.Slide18

Anti-Angiogenesis

Bevacizumab

(

Avastin) Monoclonal antibody to VEGFImproves survival in breast cancer patients with combined with TaxolApproved 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 effectsMetronomic chemotherapy: repeated, low, less than toxic doses can destroy endothelial cells and prevent angiogenesis, slowing tumor growth – works in clinical trialsSlide19

Androgen Receptor

Nuclear receptor activated by binding testosterone or

dihydrotestosterone

Closely related to PRExpressed in 75% of breast cancer and 10-20% of TNBCTNBC that express AR are molecularly similar to prostate cancer and could potentially be treated similarly.Bicalutamine: anti-androgen used to treat prostate cancer17-DMAG: semi-synthetic antibiotic derivative, has shown promise in clinical trialsEnzalutamide: androgen agonist used to treat prostate cancer; is in Phase II for TNBCSlide20

RTK Inhibitors

Suninitib

(

Sutent)Multiple-target RTK inhibitorAll PDGFRs and VEGFRsKIT (CD17) which drives the majority of all GI stromal tumors & several othersImatinib (Gleevec)Prevents phosphorolation of BCR-Abl, inhibiting signaling pathways necessary for cancer cell growthBCR-Abl: Exists only in cancer cells!Worked in vitro; no effect on metastatic breast cancer patients in Phase IISlide21

Src Tyrosine Kinase

Src

is overexpressed in breast cancer

Dasatinib: multiple tyrosine kinase inhibitor approved for CMLPossible efficacy in breast cancer - small effect seen in Phase IIIn vitro: basal breast cancer cells were more sensitive!Several others in trials also seem to have promising preclinical activitySlide22

mTOR

Cell

cycle regulator and a downstream effector in the

PI3K/PTEN/AKT pathwayPTEN is often mutated in TNBC, leading to increased AKT and mTOR activationEverolimus and temsirolimus block mTOR function and inhibit proliferationEverolimus is approved for some types of cancers - currently in clinical trials for TNBC in combination with chemotherapyTemsirolimus is approved for renal cell carcinoma and completed a Phase II trial with promising resultsSlide23

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 overexpressionHDAC (Histone deacetylase) – can effect epigenetics and cause re-expression of epigenetically silenced genesSlide24

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 apoptosisChk1 (checkpoint kinase 1): involved in cell cycle control. Inhibition sensitizes proliferating tumor cells to chemotherapies that damage DNASlide25

Mutations that Could be Targeted

p

53 (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: PTENPIK3CAAmplification of HER2Amplification of FGFR2Slide26

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 vesselsAttacks the activated endothelial cells as they divideTargets blood supply to tumors without affecting healthy tissuePrevents angiogenesis and inhibits tumor growth!!Slide27

What’s in clinical trials now?

New compounds

New drug combinations or dosing regimens

New formulationsInteresting Current Clinical TrialsRe-expression of ER in Triple Negative Breast CancersBevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast CancerLaboratory-Treated T Cells After Chemotherapy in Treating Women With Stage II or Stage III Breast Cancer Undergoing SurgeryPreoperative Clinical Trial of Sorafenib in Combination With Cisplatin Followed by Paclitaxel for Triple Negative (ER-, PR-, Her2-) Early Stage Breast CancerSlide28

Recent news stories

March 18, 2013 -

Copper depletion shows early success in triple-negative breast

cancerApril 8, 2013 – Paragazole (HDAC) excels in preclinical models of triple-negative breast cancerApril 12, 2013 - Omega-3 Fatty Acids Slow Triple-Negative Breast Cancer Cell ProliferationApril 15, 2013 - Nanodiamonds could improve effectiveness of breast cancer treatmentSlide29

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 sidesReaching complete remission and preventing recurrence are keySlide30

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