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Targeting Advanced Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and HER2 receptors. It represents 15% of breast cancers and has a higher sensitivity to chemotherapy than other subtypes. New targeted therapies are being developed and tested in clinical trials based on TNBC's defective DNA repair pathways. These include PARP inhibitors, platinum chemotherapy, and angiogenesis inhibitors. TNBC is a heterogeneous disease with multiple molecular subtypes, each with different treatment responses. Participation in clinical trials is important to advance new targeted therapies for TNBC.
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Targeting Advanced Triple-Negative Breast Cancer
- 1. Targeting Advanced Triple-Negative BreastCancer Erica L. Mayer, MD, MPH Dana-Farber Cancer Institute June 2013
- 2. Outline • Definitions: Whatis TNBC? What makes TNBC different? • Treatment: Optimizing therapy for TNBC – Chemotherapy – Biologic targeted therapy • Everything you need to know about Clinical Trials
- 3. Clinical Breast CancerSubsets Defined by IHC All Breast Cancers Triple negative 15% Burstein, Goldhirsch. St Gallen 2007. ER+ 65%-75% HER2+ 15%-20% 3
- 4. “Triple Negative” BreastCancer (TNBC) • Defined as negative for estrogen, progesterone, and HER2 receptors • Represents about 15% of all breast cancer • More likely to present in younger women (<40 years old) or in women of African American or Hispanic background • May be associated with having an inherited mutation in the BRCA1/2 genes
- 5. How to TargetAdvanced TNBC? • High growth rate • Impaired repair of DNA • Blood vessel growth Increased sensitivity to chemotherapy? Increased sensitivity to platinum chemotherapy? PARP inhibitors? Role of angiogenesis inhibitors?
- 6. TNBC Can beChemotherapy Sensitive! • Although endocrine and HER2-directed therapies not used, chemotherapy works the best against TNBC • Trials of chemotherapy suggest recent advances (addition of taxane, use of “dose dense” schedules) provide greatest benefits to TNBC vs HR+ breast cancer • A significant percentage of TNBC treated with chemotherapy before surgery completely disappear, demonstrating sensitivity to therapy • Therefore, although therapy selection for TNBC focuses on chemotherapy, this class of medicines may work best in TNBC
- 7. Chemotherapy for MetastaticBreast Cancer Many active and tolerable chemotherapy choices
- 8. Cisplatin is ofSpecial Interest for TNBC • Cisplatin: commonly used chemotherapy for many cancers (lung, esophageal, sarcoma, testicular) • Studies in metastatic breast cancer in 1980s showed it to be active, but development in breast cancer lagged • Recent interest in patients with TNBC – DNA damaging mechanism of action may be especially active against TNBC • Data from recent series of preoperative studies support significant activity in TNBC • Activity may be greater in BRCA1/2 breast cancers Sledge et al, JCO 2008; Silver et al JCO 2010; Gronwold et al, ASCO 2009
- 9. Preoperative Cisplatin AsPreoperative Therapy in Patients With BRCA1 Mutations • 25 patients with BRCA1 mutations • Stage I-III disease • Treatment: – Preoperative Cisplatin every 3 weeks x 4 doses – Mastectomy • Path CR = No invasive tumor in breast or nodes Path CR rate = 18/25 = 72% Gronwold et al, ASCO 2009
- 10. Are Platinums Preferredfor the Treatment of TNBC? • TNBC is sensitive to a wide variety of chemotherapeutic agents. • Are the tumors responding to platinum therapy the same that would have responded to other agents? • Perhaps there is selective advantage for BRCA1/2 mutation carriers as a result of impaired DNA repair? • Platinum chemotherapy is a reasonable treatment selection for metastatic TNBC
- 11. Eribulin for TNBC •Eribulin: – New chemotherapy, approved in 2010 for metastatic breast cancer – Similar to paclitaxel or vinorelbine in mechanism – Toxicities: numbness, low blood counts, some hair loss • Recent trial of eribulin vs capecitabine for metastatic breast cancer – In all patients, both drugs performed equally well, with expected toxicities for each – Patients reported improved quality of life with eribulin – Analysis of TNBC subset suggested greatest improvement in activity with eribulin in TNBC, more than in HR+ Kaufman et al, SABCS 2012; Cortes et al ASCO 2013
- 12. Novel biologic agentsfor TNBC
- 13. PARP Inhibitors: Mechanism •If BRCA1/2 is damaged or not working, the cell is dependent on PARP for all DNA repair • PARP inhibitors prevent DNA repair in cancer cells – May increase cancer cell death – May help chemo and radiation work better • PARP and BRCA1/2 normally function to repair daily DNA damage • Allows cells to grow in a healthy way • Too much DNA damage-> cell death Ellisen, Cancer Cell 2011; Tutt et al, Lancet 2010
- 14. Phase II trialof the PARP inhibitor olaparib in BRCA- deficient advanced breast cancer Study design: - To assess efficacy/tolerability of olaparib in BRCA 1/2 mutation carriers - Phase II single arm sequential cohort multicenter trial Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for advanced disease (med prior regimens = 3) Olaparib 400 mg po bid 28-day cycles; 27 patients Cohort 1 (enrolled first) Olaparib 100 mg po bid 28-day cycles; 27 patients Cohort 2 Tutt et al, ASCO 2009
- 15. Objective tumor responserate (RECIST) Overall Response Rate, n (%) Complete Response, n (%) Partial Response, n (%) 11 (41)* 1 (4) 10 (37) Olaparib 400 mg bid (n=27)ITT cohort Adverse Events: Fatigue grade 1 or 2, 56% grade 3, 15% Nausea grade 1 or 2, 26%, grade 3 11% ASCO 2009; #suppl. CRA501 • Median of 3 prior lines of chemotherapy. Substantial activity with biologic monotherapy in a heavily pretreated BRCA1/2 population!
- 16. Can we makea cancer cell more sensitive to PARP inhibition? • Reseachers at BIDMC discovered that PI3 kinase (PI3K) helps DNA repair using BRCA1 • Inhibiting PI3K decreases DNA repair; creates a unstable DNA environment similar to having a BRCA1 mutation • Experiments showed treatment with a PI3K inhibitor BKM120 increased DNA damage in cells Ibrahim et al, Cancer Discovery 2012 Exposure to BKM120 increases markers of DNA damage (pink)
- 17. Can we combinea PI3K inhibitor and PARP inhibitor? • These data suggest exposure to a PI3K inhibitor might make a cancer cell with normal BRCA1/2 more sensitive to PARP inhibition • Ongoing trial at Dana- Farber/Harvard Cancer Center is combining PI3K inhibitor BKM120 and PARP inhibitor olaparib in TNBC Juvekar et al, Cancer Discovery 2012 PARP inhibitor alone PARP inhibitor + PI3K inhibitor
- 18. • New strategies(PARP inhibitors, platinum chemotherapy) target defective DNA repair, always found in BRCA1/2 tumors • Can we identify non-BRCA1/2 tumors which also have defective DNA repair, and can be treated with PARP inhibitors? Of special interest for TNBC • HRD assay designed to find cancers which are “BRCA1/2-like” and may benefit from DNA-targeting strategies • HRD assay is performed on tumor tissue already removed from the body Can We Identify Other TNBC Sensitive to PARP inhibitors? Homologous Recombination Deficiency (HRD) Assay:
- 19. Trial of PlatinumChemotherapy before Surgery: Rate of Favorable Response by HRD Score in non- BRCA1/2 mutation carriers p = 0.0001 Telli ML, Timms K, Hartmann A-R, Ford JM, et al. SABCS 2012; abstract PD09-04 HRD negative HRD positive 70% response rate in non BRCA1/2 mutation carriers with HRD positive tumors
- 20. PARP Inhibitors inAdvanced Breast Cancer: Key Questions • Is target treatment population only BRCA1/2 carriers, or can they be useful for other breast cancer populations, ie TNBC? • Should PARP inhibitors be used alone as monotherapy, or work best in combination with chemotherapy and/or radiation therapy? • Are all of the PARP inhibitors the same, or are there differences in efficacy and safety? • Need further study in trial in advanced breast cancer
- 21. Is There aRole for Angiogenesis Inhibition in Triple Negative Breast Cancer? • Triple negative breast cancer frequently displays blood vessel tufts • Anti-angiogenic medications prevent growth of the blood vessels that cancer cells need to thrive • Does vascularity of triple negative breast cancer predict sensitivity to targeted vascular disruption? Foulkes et al, Cancer Res 2004; Nalwoga et al, BCRT 2011
- 22. Is There aRole for Angiogenesis Inhibition in Triple Negative Breast Cancer? • Trials including all breast cancer subtypes have not shown consistent activity • Analysis of TNBC subset of recent studies of bevacizumab (Avastin) has suggested possible special benefit for TNBC, more than that seen with ER+ breast cancer • Ongoing studies continue to evaluate this question Brufsky ASCO 2011; Von Minckwitz et al, NEJM 2012; Von Minckwitz et al, ASCO 2013
- 23. BATON BC: RandomizedPhase II Study of Tivozanib, a VEGF Receptor Inhibitor, in Metastatic TNBC •TNBC •No prior systemic therapy for metastatic breast cancer treatment Tivozanib +Paclitaxel Paclitaxel + Placebo • Tivozanib: oral angiogenesis inhibitor (VEGFR antagonist) • Can be combined with weekly paclitaxel chemotherapy, toxicities include high blood pressure, mild diarrhea • BATON BC trial designed to see if adding tivozanib to standard paclitaxel improves efficacy of treatment • Trial also includes scientific analysis to test a tumor signature which may identify best tumors to treat with tivozanib
- 24. What’s New inTNBC? Tumor Heterogeneity • Gene expression profile analysis from over 500 TNBC samples • 6 TNBC subgroups were identified with unique profiles Lehmann et al, JCI 2011
- 25. Heterogeneity of TNBC •Different subtypes displayed differential response to therapies in preclinical mouse models Lehmann et al, JCI 2011
- 26.
- 27. Heterogeneity of TNBC “Adisease defined by negatives is not one disease!” Andrew Tutt, MD VEGF EGFR SrcBRCA1- PARP AR
- 28. Many Agents UnderEvaluation for TNBC in Clinical Trials! Targeted Agent Target PARP inhibitors DNA repair pathways Tivozanib VEGFR, angiogenesis dasatinib Src CDK inhibitors Cell cycle control MetMab, ARQ197 Met Tigatuzumab Death receptor PI3K inhibitors PI3K mTOR inhibitors mTOR FGF inhibitors FGF Ruxolitinib JAK-1 Bicalutamide AR, androgen receptor
- 29. How Can WeDo Better? Participate in Trials! • “One reason I chose to participate in a clinical trial was to help women with triple-negative breast cancer. It is thanks to women who have enrolled in clinical trials that we have the treatments that give us hope.” – Natalia (LBBC, Guide to Understanding TNBC)
- 30. How Can WeDo Better? Participate in Trials! • Clinical trials exist for patients at any step of their breast cancer journey; trials are a part of the continuum of care • There are benefits to being on a trial! – a larger treatment team – possible exposure to cutting edge new medications – helping other patients with breast cancer • None of the advances in breast cancer could have happened without patients volunteering to be in trials!
- 31. What are clinicaltrial phases? Clinical trials are conducted in a series of steps (phases) - each phase is designed to answer a separate research question. • Phase I: Testing a new treatment in a small group of people to evaluate safety, dose, and side effects. • Phase II: Evaluating within a larger group the efficacy and safety of a new treatment • Phase III: A comparison study in a large group to determine if a new treatment works better than standard therapy. These trials typically involve randomization and may have a placebo; the data from a phase 3 trial can be used for FDA drug approval. FDA approval
- 32. Active Protocols formTNBC at DFCI Protocol ID Phase Regimen Target Key Eligibility 12-398 II Paclitaxel +/- Tivozanib VEGFR -1, -2, -3 1st line TNBC 12-024* II Ruxolitinib JAK 1/2 TNBC, pStat3+ 12-438 II BKM120 PI3K TNBC, > 2 priors 11-031 I XL765 + MSC1936369B PI3K/mTOR + MEK TNBC 11-010* I GDC-0032 PI3K TNBC > 1 prior 11-129 II MK-2206 Akt MBC any subtype with PIKCA/Akt mutation or PTEN loss 12-017 II ARQ-197 c-MET TNBC, 1-3 priors 12-430 II Cabozantinib c-MET TNBC, 0-3 priors 11-063* I LCL161 + paclitaxel IAP MBC any subtype, “signature positive” 12-084 II Veliparib/TMZ vs veliparib/carbo/taxol vs veliparib/placebo PARP MBC with BRCA 1/2 mutation; 0-1 priors
- 33. How Do IEnter a Trial? • Your provider will discuss with you trials of interest, review rationale, as well as risks and benefits • A research RN will review a consent form with you, which describes the structure and details of the trial • After a consent is signed, there is a “screening” period to determine if you are eligible • When eligibility is confirmed, then you register and can begin trial therapy
- 34. Clinical Trials: FAQs •If I consent to a trial, do I have to stay on it? – You can leave a trial at any time if either you or your provider thinks being on the trial is no longer in your best interest • Will I have to pay more to be on a trial? – All normal procedures are billed to insurance; anything beyond normal care is paid for by the trial. There should be no “upcharge” for being in a trial • Is being on a trial busy? – Each trial is different and has a different schedule • Will I know what medicine I am getting? I don’t want a placebo. – In most trials, both patient and provider know exactly what treatment is being given. – Some larger trials use randomization and placebos, and in some cases neither patient nor provider know identity of study drug. – But in almost every trial with placebo, at minimum a patient receives best standard of care.
- 35. How to learnabout trials? Or ask your provider…
- 36. Advanced TNBC: Conclusions •TNBC is a special breast cancer subgroup that requires personalized therapy • Chemotherapy works for TNBC, and has gotten better • No single best target has been identified; novel biologic agents may have activity for some subgroups • TNBC is an area of very active research; many exciting new agents in the pipeline • In the past year, 4 new metastatic TNBC trials opened at DFCI. Speak to you provider about entering a trial! • Future progress depends on.....Making every woman count!