Presentation on theme: "Chemotherapeutic Treatment Options for Triple Negative Breast Cancer"— Presentation transcript:
1 Chemotherapeutic Treatment Options for Triple Negative Breast Cancer Lauren BarneyApril 17, 2013
2 Breast Cancer Subtypes Breast cancer is classified into clinical subtypes based upon receptor expressionThese subtypes dictate possible therapeutic options and vary in their prognosisLuminal: derived from the luminal cellsER+, PR+Can use hormonal therapyLess aggressiveBasal: derived from myoepithelial cellsER-, PR-No specific target for therapiesMore aggressiveHER2-enrichedLuminal ALuminal BClaudin-LowHER2-enrichedBasalER: estrogen receptorPR: progesterone receptorHER2: human epidermal growth factor receptor 2
3 Luminal and Basal Characteristics Basement membraneMyoepithelial Cells BasalLuminal Cells LuminalBasalLuminalLow ERLow HER2High CK5/6c-KIT higherHigh EGFRHigh p53 mutationHigh p53 proteinHigh cyclin EVery high vimentinHigh ERHigher HER2Low CK5/6Low c-KITLow EGFRLow p53 mutationLow p53 proteinLow cyclin ELow vimentinCyclin E: Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines cell divisionVimentin: type III intermediate filament protein that is expressed in mesenchymal cells. EMT marker
4 Triple Negative Breast Cancer 15-25% of all breast cancer, but much higher proportion of all breast cancer mortalityLack ER, PR and HER2 – no targeted therapiesMuch 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 survivalTN tumors have specific morphologic characteristics: elevated mitotic count, tumor necrosis, pushing margin of invasion, and stromal lymphocytic response and high nuclear-cytoplasmic ratioNot all basal are TN
5 TN vs Basal SubtypesThe 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.
6 Treatments can be targeted for cancers that express hormonal receptors or HER2; TN remains a clinical challenge.Hormonal therapy: blocks estrogen activityTamoxifen, 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.Tamoxifen
7 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!
8 TNBC TreatmentChemotherapy 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, idarubicinOxazophorine: DNA alkylating agentCyclophosphamide (C)
9 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 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)
10 CMF therapy may actually reduce recurrence of TNBC compared to anthracycline or taxane-based treatmentCMF 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 possible
11 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 TNBCBosch et al. / Cancer Treatment Reviews 36 (2010) 206–215Basal-like and HER2+/ER subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers. Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype. The poorer prognosis of basal-like and HER2+/ER breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved.
12 Beyond brute force chemo: What are some potential treatment options for TNBC? Current and developing therapiesMany in clinical trialsMost target proliferative pathwaysTargets: General proliferation, surface molecules, secondary messengers
14 Platinum AgentsPlatinum agents can bind to DNA and cause cross-linking to occur cell deathCisplatin, carboplatin and oxaplatin are approved for some types of cancers and are being studied as treatments for TNBC
15 PARP Inhibitors PARP: poly ADP ribose polymerase Involved in DNA repair by detecting single-strand breaksCan 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.
16 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!
17 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.
18 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 trials
19 Androgen ReceptorNuclear receptor activated by binding testosterone or dihydrotestosteroneClosely 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 TNBC
20 RTK Inhibitors Suninitib (Sutent) Imatinib (Gleevec) 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 II
21 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 activity
22 mTORCell 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 results
23 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 genes
24 Other ways to sensitize cells to chemotherapy Inhibition of TGF-beta sensitizes to chemoTRAIL: 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 DNATGFbeta: controls prolif in normal cells; not cancer cells.Trail induces apoptosis
25 Mutations that Could be Targeted p53 (75% of TNBC) – complex, so target downstream components of pathwayMyc (40% of TNBC)Loss of retinoblastoma gene (20% of TNBC)Mutation in BRCA1 or BCRA2 (15-20% of TNBC)Rare:PTENPIK3CAAmplification of HER2Amplification of FGFR2RB: tumor suppressor
26 We need to get creative: changes in formulation EndoTAG®-1: formulation of paclitaxel combined with neutral and positive lipidsInteracts 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!!
27 What’s in clinical trials now? New compoundsNew drug combinations or dosing regimensNew 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 CancerClinicaltrials.gov
28 Recent news storiesMarch 18, Copper depletion shows early success in triple-negative breast cancerApril 8, 2013 – Paragazole (HDAC) excels in preclinical models of triple-negative breast cancerApril 12, Omega-3 Fatty Acids Slow Triple-Negative Breast Cancer Cell ProliferationApril 15, Nanodiamonds could improve effectiveness of breast cancer treatment
29 Outlook for now and future Need targeted therapies, new formulations to be able to treat TNBCCombination therapies will be necessary because tumors are heterogeneous and can changeAlso need to attack tumors from all sidesReaching complete remission and preventing recurrence are key
30 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: 235–44Pal et al. Triple negative breast cancer: unmet medical needs. Breast Cancer Res Treat (2011) 125:627–636Crown et al. Emerging targeted therapies in triple-negative breast cancer. Annals of Oncology 23 (Supplement 6): vi56–vi65, 2012Oncology (Williston Park) October ; 22(11): 1233–1243.Hudis and Gianni. Triple-Negative Breast Cancer: An Unmet Medical Need. The Oncologist 2011, 16:1-11. doi: /theoncologist.2011-S1-01Lisa A. Carey, E. Claire Dees, Lynda Sawyer, et al. Clin Cancer Res 2007;13:Turner N et al. Targeting triple negative breast cancer: Is p53 the answer? Cancer Treat Rev (2013), /j.ctrv