Update on Breast Cancer William J. Gradishar, MD Professor of - PowerPoint PPT Presentation

Update on Breast Cancer William J. Gradishar, MD Professor of Medicine Robert H. Lurie Comprehensive Cancer Center Feinberg School of Medicine Northwestern University

Overview  PARP Inhibitors  Neoadjuvant Therapy in BRCA+ BC  SLNB and Auxillary Recurrence  Endocrine Therapy Studies  Metastatic Breast Cancer Therapy – DM-1 – Neratanib – RIBBON-1

PARP Inhibitors

PARP-1 is a key enzyme involved in repair of single strand DNA breaks DNA single strand break (SSB) damage • PNK 1 • XRCC1 • pol β Inhibition of PARP-1 • LigIII prevents recruitment of • PARP DNA repair enzymes leads to failure of SSB repair During S-phase, -accumulation replication fork of SSBs is arrested at site of SSB Degeneration into double strand breaks

Selective effect of PARP-1 inhibition on cancer cells with BRCA1 mutation • DSB in DNA • Normal cell • BRCA-deficient cancer cell Triggers activation Deficient HR repair of HR Increases DSB that pathway to can’t be repaired repair DSB • Genomic • Cell instability survival and apoptosis • HR – homologous recombination; DSB – double strand break

PARP Inhibitor Mechanism of Action 1. PLATINUM CHEMOTHERAPY Inflicts DNA damage via adducts and DNA crosslinking CG CG CG CG PARP1 AT AT T BSI-201 T PARP1 4. REPLICATION 3. INHIBITION OF FORK COLLAPSE TA PARP1 TA Double strand DNA PARP1 2. PARP1 C Disables DNA break CG UPREGULATION G base-excision GC Base-excision repair A repair A of DNA damage BRCA1 BRCA2 Cell Survival Cell Death O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.

Triple Negative BC Shares Clinical and Pathologic Features with BRCA1-Related BC Triple Negative/Basal-Like 1,2,3 Characteristics Hereditary BRCA1 ER/PR/HER2 status Negative Negative TP53 status Mutant Mutant BRCA1 status Mutational inactivation* Diminished expression* Gene-expression pattern Basal-like Basal-like Tumor histology Poorly differentiated Poorly differentiated (high grade) (high grade) Chemosensitivity to Highly sensitive Highly sensitive DNA-damaging agents *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4 4 1. Perou C, et al. Nature. 2000;408:747-752. 2. Cleator S, et al. Lancet Oncology. 2007;8:235-244. 3. Sorlie T, et al. Proc Natl Acad Sci USA. 2001;98:10569-10674. 4. Miyoshi Y, et al. Int J Clin Oncol. 2008;13:395-400. O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.

Phase II TNBC Study: Treatment Schema BSI-201: Metastatic TNBC N = 120 small molecule PARP inhibitor RANDOMIZE BSI-201 (5.6 mg/kg, IV, d 1,4,8,11) Gemcitabine (1000 mg/m 2 , IV, d 1,8) 21-Day Gemcitabine (1000 mg/m 2 , IV, d 1,8) Cycle Carboplatin (AUC 2, IV, d 1,8) Carboplatin (AUC 2, IV, d 1,8) Restaging Every 2 Cycles * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.

BSI-201: Preliminary Efficacy Results* Gem/Carbo BSI-201 +Gem/Carbo P -value (n = 44) (n = 42) Objective Response Rate, n (%) 7 (16) 20 (48) .002 **Clinical Benefit Rate, n (%) 9 (21) 26 (62) .0002 * Includes patients enrolled before September 30, 2008 and patients who had a confirmed response or disease progression **Clinical Benefit Rate = CR + PR + SD ≥ 6 months O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.

BSI-201: Conclusions  PARP1 was upregulated in most evaluated TNBC patients  BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities  BSI- 201 improved patients’ clinical outcomes – Clinical Benefit Rate (62% vs. 21%; P = .0002) – ORR (48% vs 16%; P = 0.002) – Median PFS (6.9 months vs. 3.3 months; P < 0.0001) – Median OS (9.2 months vs. 5.7 months; P = 0.0005) Promising safety and efficacy data from this Phase II study justify further investigation of BSI-201 in a Phase III study O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.

Phase II Study with Olaparib: Rationale and Design  To assess the efficacy and tolerability of oral olaparib in BRCA1/BRCA2 mutation carriers with breast cancer  Multicenter proof-of-concept phase II study, single-arm sequential cohort design Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure ≥1 prior chemotherapy for advanced disease Cohort 1 (enrolled first) Cohort 2* Olaparib 400 mg po BID (MTD) Olaparib 100 mg po BID 28-day cycles; n = 27 28-day cycles; n = 27 *Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg BID cohort were permitted to crossover to receive the 400 mg bid dose MTD: determined during Phase I evaluation Tutt A, et al. ASCO 2009. Abstract 501.

Olaparib: Efficacy Results ITT cohort Olaparib 400 mg bid Olaparib 100 mg bid (n = 27) (n = 27) Overall Response Rate, n (%) 11 (41)* 6 (22)* Complete Response, n (%) 1 (4) 0 Partial Response, n (%) 10 (37) 6 (22) *An additional 1 patient in the 400 mg cohort and 3 patients in the 100 mg cohort had unconfirmed responses Per protocol cohort 400 mg bid 100 mg bid (n = 26) (n = 24) 6 (25) † Overall Response Rate, n (%) 11 (42) Complete Response, n (%) 1 (4) 0 Partial Response, n (%) 10 (39) 6 (25) † An additional 3 patients in the 100 mg cohort had unconfirmed responses Tutt A, et al. ASCO 2009. Abstract 501.

Olaparib: Conclusions  First report of a targeted therapy trial designed for BRCA1/BRCA2 carriers with breast cancer  Single agent oral olaparib 400 mg bid has substantial activity in heavily pre-treated BRCA1/BRCA2 carriers with advanced breast cancer – Objective response rate ITT (RECIST): 41% – Median PFS: 5.7 months  Oral olaparib is well tolerated in BRCA1/BRCA2 carriers with a similar side effect profile to prior experience in non-carriers  Clinical proof-of-concept for targeting BRCA1/BRCA2 mutations in both breast and ovarian 1,2 cancer

Neoadjuvant Therapy in BRCA+ Breast Cancer

Neoadjuvant Study: Design S BRCA1 Mutation U Cisplatin 75mg/m2 Carriers R AC q 3wks IV x 4 cycles Primary Breast G Cancer E R N = 10 Y 25 Primary Endpoint: pCR (in breast and axilla, DCIS permitted) Gronwald J, et al. ASCO 2009. Abstract 502.

Neoadjuvant Study: Response to Treatment Response No. % Clinical response Complete response 18 72 Partial response 7 28 No change 0 0 Progressive disease 0 0 Pathologic response Complete pathologic response 18 72 Partial response 7 28 No response 0 0 Residual disease in breast None 19 76 < 1 cm 0 0 1-5 cm 6 24 > 5 cm 0 0 Number of lymph nodes positive 0 21 84 1-3 4 16 4-9 0 0 >9 0 0 Gronwald J, et al. ASCO 2009. Abstract 502.

Neoadjuvant Study: Conclusions  Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers  Choice of breast cancer treatment may be better with BRCA1 testing Gronwald J, et al. ASCO 2009. Abstract 502.

Sentinel Lymph Node Biopsy and Auxillary Recurrence

Omission of Axillary Therapy in Patients with pN1mi or pN0i+ by Sentinel Node Biopsy: the MIRROR Study • Patients with favorable • primary tumor characteristics • N = 2680 after • No indication for adjuvant central pathology • systemic therapy review • Sentinel node procedure • pN0, pN0(i+) or pN1mi • Completion axillary • Axillary radiotherapy • Sentinel node biopsy • lymph node dissection • only (SN only) • (axRT) • (cALND) N = 1314 N = 1218 N = 148 • Patients selected from the Netherlands Cancer Registry (1998-2005) (N = 3205) • Median follow-up: 4.7 years Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).

Omission of Axillary Therapy in Patients with pN1mi or pN0i+ by Sentinel Node Biopsy: the MIRROR Study Results: Multivariate Analysis Sentinel node Axillary N 5-yr axillary HR 95 % CI status therapy recurrence cALND 125 1.6% 1.00 Reference pN0 0.23 – 4.98 SN only 732 2.3% 1.08 cALND/axRT 450 0.9% 1.00 Reference pN0 (i+) 0.67 – 8.48 SN only 345 2.0% 2.39 cALND/axRT 887 1.0% 1.00 Reference pN1mi 1.46 – 13.24 SN only 141 5.0% 4.39* • HR corrected for age, tumor size, grade, hormone receptor status, adjuvant systemic therapy and radiotherapy to the breast • * Statistically significant compared to cALND/axRT Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).

Omission of Axillary Therapy in Patients with pN1mi or pN0i+ by Sentinel Node Biopsy: the MIRROR Study Conclusions − Omission of axillary therapy appears feasible in pN0 disease − Axillary therapy non-significantly decreased axillary recurrence in those with pN0(i+) disease − Axillary therapy significantly decreased axillary recurrence in those with pN1mi disease − Patients who received axRT showed no axillary recurrence, although number of events was too small for statistical analysis − Tumor size, histological grade III, and negative ER/PgR status were significantly predictive of 5-year axillary recurrence by multivariate analysis Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).

Endocrine Therapy Studies: CYP2D6 Inhibition