Joyce O'Shaughnessy, MD Co-Director, Breast Cancer Research ProgramBaylor-Charles A Sammons Cancer CenterTexas Oncology, PAUS OncologyDallas, Texas. Eric P Winer, MDThompson Investigator in Breast Cancer ResearchChief, Division of Women's Cancers Dana-Farber Cancer InstituteProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts.
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1. RTP TV: An 8-Part Live CME Webcast Series
3. Disclosures for Moderator Neil Love, MD
4. Disclosures for Joyce O’Shaughnessy, MD
5. Disclosures for Eric P Winer, MD
6. RTP TV: An 8-Part Live CME Webcast Series
7. Survey of 100 Practicing Oncologists 95% – fraction who see patients with TNBC
10 – median number of patients with metastatic TNBC currently in their practices
8. Survey of 100 Practicing Oncologists Fraction with a patient who has received…
Iniparib – 23%
Olaparib – 16%
Veliparib – 7%
9. Survey of 100 Practicing Oncologists If you were to attend a CME conference on breast cancer, to what extent would you be interested in learning about the following topics?
Response scale 0 – 10
0 = no interest
10 = very interested
10. TNBC: New Agents and Regimens
11. TNBC: PARP Inhibitors
12. Survey of 100 Practicing Oncologists What question(s) would you like to pose to a clinical investigator with expertise in the management of TNBC?
97 questions/cases received
13. When will newer agents be integrated into earlier lines of treatment?
14. When is BRCA testing indicated in a patient with TNBC?
15. Under what conditions should metastatic sites be biopsied?
16. Are there other new noncytotoxic, targeted agents in TNBC in addition to PARP inhibitors?
— Naples, FL
18. Case 1 (Dr O’Shaughnessy) 50 yo woman with basal-like TNBC
Preoperative AC ? paclitaxel: pCR • Tumor “melts away” after 1 cycle of AC
2 years later, very rapidly growing ipsilateral internal mammary node protruding from her chest and invading sternum and mediastinal LNs
Patient enrolls on a trial of gem/carbo ± iniparib*
Major response for 8 cycles (6 months)
Tissue harvested for total genome sequencing
Response for 6 months but progressing
19. Progression with Regrowth of Ipsilateral Mammary Mass and Mediastinal Nodes
20. Phase II Study of Iniparib plus Gemcitabine/Carboplatin in mTNBC
21. A Randomized Phase III Study of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Metastatic Triple-Negative Breast Cancer (mTNBC) O’Shaughnessy J et al. Proc ASCO 2011;Abstract 1007.
22. Phase II Study of Iniparib plus Gemcitabine/Carboplatin in mTNBC
23. Metastatic Triple-Negative Breast Cancer (mTNBC) 15% of breast cancers; clinically defined as ER-negative, PR-negative and HER2-non-overexpressing
Heterogeneous disease with generally virulent natural history
Shares gene expression profiles with basal-like, claudin-low and other molecular subtypes
No clinical implications of molecular subtypes at present
24. Iniparib (BSI-201)
A novel, investigational, anticancer agent
In triple-negative breast cancer cell lines:
Induces cell cycle arrest in the G2/M phase
Induces double strand DNA damage ?H2AX foci but does not inhibit PARP1 and 2 at physiologic drug concentrations
Potentiates cell-cycle arrest induced by DNA damaging agents, including platinum and gemcitabine
Physiologic targets of iniparib and its metabolites are under investigation
25. Preclinical Pharmacodynamic and Pathway Analysis of 3 Presumed PARP Inhibitors: ABT-888, AZD2281, BSI-201 ABT-888 and AZD2281 are mediated by PARP1 or PARP2.
Iniparib (BSI-201) suppressed genes in the telomere pathway, suggesting PARP5/6 as potential targets.
27. Study Objectives Primary:
Overall survival (OS)
Progression-free survival (PFS)
Study considered positive if either endpoint met
Objective response rate (ORR)
Safety, tolerability and pharmacokinetics of GCI
28. Treatment-Emergent Adverse Events Safety Population (Prior to crossover, >5% Grade 3/4 in GCI arm)
36. Deconstructing the molecular portraits of breast cancer
41. Case 2 (Dr Winer) 48 yo premenopausal, BRCA1/2-negative woman presents 6 years ago with weakly ER+, PR- T2N1 breast cancer
Neoadjuvant AC ? paclitaxel
Excision/re-excision plus RT
Ipsilateral breast recurrence 1 year later
Waxing and waning supraclavicular adenopathy over next 18 months until diagnosed with local recurrence
Needle biopsy reveals metastatic TNBC, with small pulmonary nodule
Enrolled on TBCRC009: Phase II study of cisplatin or carboplatin for metastatic TNBC*
Clinical CR after 7 cycles of cisplatin
Treatment discontinued due to toxicity (fatigue, neuropathy)
No further therapy for past 2 years, 4 months
43. TBCRC009: A Multicenter Phase II Study of Cisplatin or Carboplatin for Metastatic Triple-Negative Breast Cancer and Evaluation of p63/p73 as a Biomarker of Response
44. Phase II Study of Cisplatin or Carboplatin for mTNBC 86 patients enrolled to physician's choice of either cisplatin or carboplatin
Overall RR: 30.2%, including 4 CR (4.7%) and 22 PR (25.6%)
RR by treatment (exploratory): 37% cisplatin
p63/p73 analysis is ongoing
45. Submitted Case Dr Frances de la Serna, Philippines 40 yo woman with axillary lymphadenopathy in 1/2010
Excisional biospy: Ductal carcinoma consistent with breast primary in 4 nodes
Ultrasound: 2 solid masses in breast (15.1 and 20.9 mm)
Neoadjuvant anthracycline/taxane-based therapy x 2 cycles ? surgery
No residual tumor or LVI in the breast
7/9 nodes positive
ER/PR-, HER2 1-2+ (FISH positive)
46. Submitted Case (Continued) 12/2010: Neck mass
FNB: Metastatic carcinoma
Multiple enlarged lymph nodes in supraclavicular and jugular chains
Excisional biopsy: ER/PR/HER2-negative adenocarcinoma
Patient receives cisplatin/gemcitabine
Resolution of enlarged nodes
5/2011: Neck mass
Biopsy: Metastatic carcinoma
Multiple nodules on the skin flap
Plan: Continue cisplatin
47. Local versus Central Laboratory Discrepancies in TNBC Status (CIBOMA/2004-01/GEICAM/2003-11) N = 1,441 patient samples sent for central laboratory confirmation
In 130 cases (9%) tumors were found to not be TNBC by central determination
71% of discrepant results involved ER or PR status
22% of discrepant results involved HER2 status
51. TBCRC 018: Phase II Study of Iniparib plus Chemotherapy to Treat Triple-Negative Breast Cancer (TNBC) Brain Metastases (BM) Anders CK et al.
Proc ASCO 2011;Abstract TPS127: Trials in Progress.
54. Case 3 (Dr O’Shaughnessy) A woman in her mid-50s with locally advanced and metastatic TNBC
Enrolled in a study of total genome sequencing
Determined to have a high level BRAF amplicon
Enrolled on a Phase I trial of MEK plus AKT inhibitors*
Significant response in a very large, fungating breast
58. A Phase I Dose-Escalation Study of Oral MK-2206 (Allosteric AKT Inhibitor) with Oral Selumetinib (MEK Inhibitor) in Patients with Advanced or Metastatic Solid Tumors
61. Schedule of Events