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Breast Cancer Highlights From San Antonio

Breast Cancer Highlights From San Antonio. Joyce O'Shaughnessy, MD Kimberly Blackwell, MD Hope Rugo , MD. Reminder: feedback is appreciated. You will be prompted at the end for your feedback. Updates on Chemotherapy and Other Novel Agents. Joyce O'Shaughnessy, MD. Adjuvant Chemotherapy.

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Breast Cancer Highlights From San Antonio

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  1. Breast Cancer Highlights From San Antonio Joyce O'Shaughnessy, MD Kimberly Blackwell, MD Hope Rugo, MD

  2. Reminder: feedback is appreciated. You will be prompted at the end for your feedback.

  3. Updates on Chemotherapy and Other Novel Agents Joyce O'Shaughnessy, MD

  4. Adjuvant Chemotherapy

  5. CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence • Rationale: • Isolated local or regional recurrence (ILRR) of breast cancer has a poor prognosis • No randomized studies of adjuvant chemotherapy for ILRR have been published in the last 30 years • Objective: Evaluate the effect of adjuvant chemotherapy on patients with ILRR • CALOR study design: • Chemotherapy chosen by investigators • Recommendation: at least 2 drugs, 3-6 months of therapy (N=162) + Endocrine therapy for HR-positive disease + HER2-directed therapy (optional) + Radiation therapy (mandatory for those with positive margins) RANDOMI ZE • Eligibility criteria: • First ILRR • Complete gross excision of recurrence • No evidence of positive supraclavicular LNs • No evidence of distant metastasis Adjuvant chemotherapy No chemotherapy Primary endpoint: DFS Secondary endpoint: OS Aebi et al., SABCS 2012; abstract S3-2

  6. CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence • Sample size: • Original target was 977 patients and HR = 0.74 • Amended in 2008; target was 265 patients and HR = 0.60 • Actual enrollment: 162 patients • Results: * 42% of patients in the chemotherapy arm and 32% in the no-chemotherapy arm had not received previous chemotherapy. The median time from primary surgery to ILRR was 5 and 6 years, respectively. Aebi et al., SABCS 2012; abstract S3-2

  7. CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence • Efficacy results: • Multivariate analysis showed treatment (chemo/no chemo) to have significant impact on both DFS (HR = 0.50; P = .01) and OS (HR = 0.37; P = .02) Aebi et al., SABCS 2012; abstract S3-2

  8. UK TACT2: Comparison of Standard vs Accelerated Epirubicin in Early Breast Cancer • The objective was to test the following 2 hypotheses: • Acceleration of anthracycline chemotherapy offers improved efficacy (these results presented here) • Capecitabine has similar efficacy but less toxicity compared with CMF • UK TACT2 Phase III trial with 2x2 factorial study design: RANDOMIZATION (N=4391) • Standard epirubicin (E) • 100 mg/m2, q3w, for 4 cycles • followed by: • Accelerated epirubicin (aE) • 100 mg/m2, q2w, for 4 cycles • Pegfilgrastim 6 mg on day 2 • followed by: • CMF • 600/40/600 mg/m2 • IV bolus, days 1 & 8 or 100/40/600 mg/m2 PO, days 1-14, for 4 cycles • CMF • 600/40/600 mg/m2 • IV bolus, days 1 & 8 or 100/40/600 mg/m2 PO, days 1-14, for 4 cycles • Capecitabine (X) • 2500 mg/m2 bid, days 1-14, for 4 cycles • Capecitabine (X) • 2500 mg/m2 bid, days 1-14, for 4 cycles Primary endpoint: TTR (time to tumor recurrence) Secondary endpoints: DFS, OS, toxicity, QOL Cameron et al., SABCS 2012; abstract S3-3

  9. UK TACT2: Comparison of Standard vs Accelerated Epirubicin in Early Breast Cancer • Safety results: • Efficacy results: • There were 167 breast cancer deaths in the E arm and 179 in the aE arm Cameron et al., SABCS 2012; abstract S3-3

  10. 10-Year Follow Up of Intense Dose-Dense Chemotherapy vs. Conventional Chemotherapy in High-Risk Patients with ≥4 Positive LNs • Rationale: There are no published reports of long-term survival and toxicity data with dose-dense regimens • Objective: Confirm the Norton-Simon hypothesis of dose density and evaluate the safety of epoetinalfa as primary prophylaxis • Study design: cyclophosphamide 2500 mg/m2 q2w x 3 epirubicin 150 mg/m2 q2w x 3 paclitaxel 225 mg/m2 q2w x 3 (N=1284) RANDOMI ZE + tamoxifen G-CSF ± epoetinalfa + tamoxifen EC 90/600 mg/m2 q3w x 4 paclitaxel 175 mg/m2 q3w x 4 Primary endpoint: RFS Secondary endpoint: OS, QOL, toxicity Moebus et al., SABCS 2012; abstract S3-4

  11. 10-Year Follow Up of Intense Dose-Dense Chemotherapy vs. Conventional Chemotherapy in High-Risk Patients with ≥4 Positive LNs • Efficacy results: • No therapy-related death or long-term toxicity was observed with iddETC • Transfusion results: • Negative impacts of epoetinalfa on RFS and OS were not observed Moebus et al., SABCS 2012; abstract S3-4

  12. BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer • BEATRICE study design (N=2591) 4-8 cycles of standard chemotherapy (investigator’s choice) RANDOMI ZE • Eligibility criteria: • Resected triple-negative (centrally confirmed) invasive early breast cancer 4-8 cycles of standard chemotherapy (investigator’s choice) + bevacizumab 5 mg/kg/wk equivalent for 1 year duration Primary endpoint: DFS Secondary endpoints: OS, breast cancer-free interval, DFS, distant DFS, safety, biomarkers • Chemotherapy options: • Taxane-based (≥4 cycles) • Anthracycline-based (≥4 cycles) • Anthracycline + taxane (3-4 cycles each) Cameron et al., SABCS 2012; abstract S6-5

  13. BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer • Efficacy results • None of the subgroups examined (age, baseline ECOG performance status, region, race, menopausal status, tumor size, # of positive LNs, adjuvant chemotherapy, HR status, and surgery) showed a significant effect on invasive DFS • Safety results Cameron et al., SABCS 2012; abstract S6-5

  14. BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer • Grade ≥3 AEs of special interest by treatment phase • 5%-8% of patients taking bevacizumab + an anthracycline-based regimen experienced an LVEF decline, and ~1% experienced class III/IV CHF. Over 80% of these AEs resolved at the time of data cut-off Cameron et al., SABCS 2012; abstract S6-5

  15. BEATRICE Trial: Biomarker Results • Biomarker analysis performed to investigate potential predictive markers of benefit from adjuvant bevacizumab • Sub-study included 45% of total patient population • Evaluated correlation of biomarkers with invasive disease-free survival * HR <1.0 indicates CT plus Bev better than CT alone Carmeliet et al., SABCS 2012; abstract P3-06-34

  16. NCCN Analysis of Leukemia Diagnoses in Breast Cancer Patients • Rationale: • Adjuvant therapy provides great benefit but also infrequently causes leukemia • Objective: • Examine the incidence of leukemia among breast cancer survivors • Identify clinical characteristics of women with breast cancer who develop leukemia • Stage I-III breast cancer diagnosis at NCCN (July 1997 – Dec 2008) • N=22,248 • Prior history of cancer • n=1715 excluded First diagnosis of breast cancer n=20,533 Censored at date of last NCCN contact n=16092 • Censored at first date of other cancer event • n=3935 • Died while being followed at NCCN • n=455 Patients with leukemia n=51; 0.25% Patients without leukemia, n=20,482 Karp et al., SABCS 2012; abstract S3-5

  17. NCCN Analysis of Leukemia Diagnoses in Breast Cancer Patients *Chemotherapy Regimens Included: 4 Cycles: AC or EC, FA50C or FE100C, TC 6 Cycles: CMF, CAF, TAC, FA50C or FE100C Karp et al., SABCS 2012; abstract S3-5

  18. NCCN Analysis of Leukemia Diagnoses in Breast Cancer Patients • Characteristics of leukemia cohort: • Hazard ratios for risk of developing leukemia: • Incidence of developing leukemia: • 0.32% at 5 years • 0.52% at 10 years Karp et al., SABCS 2012; abstract S3-5

  19. Metastatic Breast Cancer

  20. Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer • Study 301 global, open-label design (N=1102) Eribulin 1.4 mg/m2, days 1 & 8, q3w • Eligibility criteria: • Locally advanced or metastatic breast cancer • 0-3 prior chemotherapies (≤ 2 for advanced disease) • Prior anthracycline and taxane • Refractory to most recent chemotherapy RANDOMI ZE Capecitabine 1250 mg/m2 BID PO, days 1-14, q3w Primary endpoint: OS and PFS Secondary endpoints: QOL, ORR, duration of response, 1-, 2-, 3-yr survival rates, tumor-related symptom assessments, safety parameters, population PK Final analysis declared positive if either eribulin OS significantly better than capecitabine OS or eribulin PFS significantly better than capecitabine PFS and if OS HR < 1.0 Kaufman et al., SABCS 2012; abstract S6-6

  21. Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer • Study 301 efficacy results • Pre-specified exploratory analyses suggest that 3 subgroups may have increased therapeutic benefit with eribulin: Triple-negative (HR 0.70, 0.55-0.91) • ER-negative (HR 0.78, 0.64-0.96) • HER2-negative (HR 0.84, 0.72-0.98) Kaufman et al., SABCS 2012; abstract S6-6

  22. Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer • Study 301 safety results Kaufman et al., SABCS 2012; abstract S6-6

  23. Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer • Study 301 hematologic AEs Kaufman et al., SABCS 2012; abstract S6-6

  24. Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer • Study 301 non-hematologic AEs Kaufman et al., SABCS 2012; abstract S6-6

  25. Phase II Trial of EribulinMesylate as First-Line Therapy for HER2- Locally Recurrent or Metastatic Breast Cancer • Eribulin: 1.4 mg/m2 days 1, 8 every 3 weeks • 48 patients enrolled * CBR = CR + PR + durable SD Vahdat et al., SABCS 2012; abstract P1-12-02

  26. Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for MBC with Poor Prognostic Factors • Retrospective analysis of the efficacy and safety of patients with poor prognostic factors (DFI ≤ 2 years or visceral-dominant metastases) who received first-line treatment in 2 previous randomized trials. P=.020 P<.001 P=.002 P<.001 O’Shaughnessy et al., SABCS 2012; abstract P1-12-07

  27. Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for MBC with Poor Prognostic Factors O’Shaughnessy et al., SABCS 2012; abstract P1-12-07

  28. Impact of BRCA1/2 Mutation Status on Response to Platinum-Based Chemotherapy in Triple-Negative Breast Cancer in the TBCRC009 Trial • The TBCRC009 phase II trial evaluated single-agent cisplatin or carboplatin as first- or second-line therapy for metastatic TNBC • 6 patients (7%) are long-term survivors who achieved durable responses and remain off all therapy (22+ - 53+ months); all of these patients are BRCA1/2 WT (5) or unknown (1), and received platinum therapy as first-line treatment for MBC * P=.079 versus BRCA1/2 WT Isakoff et al., SABCS 2012; abstract PD-09-03

  29. Neoadjuvant Chemotherapy

  30. Neoadjuvant Chemotherapy in Breast Cancer Patients ≤ 35 Years Old • Rationale: • Previous studies have shown that patients who are diagnosed with breast cancer at a young age have distinctly different disease characteristics, including pCR rate,1 biomarker profile,2 and prognosis3,4 • Objective: Compare the impact of age on pCR (pathologic complete response) rate, DFS, LRFS (local recurrence-free survival), and OS in patients receiving neoadjuvant chemotherapy for breast cancer • Study design: • A meta-analysis was performed on 8 neoadjuvant trials describing almost 9000 patients • Patients were divided into 3 age groups: • ≤ 35 (n=704) • 36-50 (n=4167) • ≥ 51 (n=4078) 1Huober et al. Breast Cancer Res Treat. 2010;124:133-40 2Colleoni et al. Ann Oncol. 2002;13:273-9 3Kroman et al. BMJ. 2000;320:474-8 4Anders et al. J ClinOncol. 2008;26:3324-30 Loibl et al., SABCS 2012; abstract S3-1

  31. Neoadjuvant Chemotherapy in Breast Cancer Patients ≤ 35 Years Old • pCR rate results: • pCR rates were significantly higher in patients ≤35 years old (23.6%) compared with those 36-50 (17.5%) and with those ≥ 51 (13.5%; P < .0001) • Age was an independent predictor of pCR for those patients with HR-positive, HER2-negative or triple-negative (TNBC) tumors • For patients ≤35 years old with HR-positive, HER2-negative tumors, a pCR predicted better DFS • Survival results: • Very young patients had significantly worse DFS and LRFS, but not OS, when compared with either of the older age groups Loibl et al., SABCS 2012; abstract S3-1

  32. Clinical Implications • ‘Adjuvant’ chemotherapy may benefit ER-negative patients with treated locoregional recurrence • Leukemia risk may be 0.5% at 10 years after adjuvant anthracycline or cyclophosphamide chemotherapy • Eribulin effective after A/T early in MBC treatment. Efficacy in TNBC promising • First-line eribulin is safe and active • Nab-paclitaxel retains efficacy in poor-prognosis MBC patients • Platinum has activity in mTNBC and some first-line patients can have very durable response

  33. Advances in the Treatment of ER+ Breast Cancer Kimberly Blackwell, MD

  34. Adjuvant Therapy

  35. Relative Effectiveness of Letrozolevs Tamoxifen for Lobular Cancer in BIG 1-98 Cohort • Rationale: • Most classic lobular carcinoma is HR-positive and HER2-negative • However, limited data are available regarding the use of letrozole in classic lobular cancers • Objective: Evaluate the effectiveness of adjuvant letrozole compared with adjuvant tamoxifen in patients with lobular cancer (broken down by Luminal A and Luminal B subtypes) enrolled in the BIG 1-98 trial • Patient cohort: • Patients from BIG 1-98 with postmenopausal HR-positive disease receiving 5 years of letrozole or 5 years of tamoxifen (n=4922) • Patients eligible for this analysis with HR-positive, HER2-negative disease: • Ductal histology (n=2,599): 55.3% Luminal A, 44.7% Luminal B • Classic lobular histology (n=324): 73.1% Luminal A, 26.9% Luminal B Filho et al., SABCS 2012; abstract S1-1

  36. Relative Effectiveness of Letrozolevs Tamoxifen for Lobular Cancer in BIG 1-98 Cohort • Ductal DFS results: • Lobular DFS results: • Luminal A/B DFS results: • Luminal A disease showed an interaction P-value of .049 for DFS • Luminal B disease was not significant for DFS (P = .23) Interaction P-value: .03 Filho et al., SABCS 2012; abstract S1-1

  37. Relative Effectiveness of Letrozolevs Tamoxifen for Lobular Cancer in BIG 1-98 Cohort • Multivariate analysis for DFS: • Interactions: • Treatment by histology (ductal vs. lobular): P = .006 • Treatment by subtype (Luminal A vs. Luminal B): P = .01 • Multivariate analysis for OS: • Interaction: treatment by histology: P = .035 Filho et al., SABCS 2012; abstract S1-1

  38. ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis • Rationale: • An EBCTCG meta-analysis has shown that 5 years of adjuvant tamoxifen produces a lower risk of breast cancer death compared with no tamoxifen (23.6% vs. 32.7% at 15 years, P < .00001)1 • Treatment with 5 years of tamoxifen is currently the standard hormonal therapy for premenopausal women with early-stage, ER-positive breast cancer • Objective: Estimate the effect of 10 years of tamoxifen on ER-positive breast cancer recurrence and mortality compared with 5 years of tamoxifen • ATLAS study design: (N = 6846) RANDOMI ZE Discontinue tamoxifen • Eligibility criteria: • ER-positive breast cancer • Completed 5 years of tamoxifen therapy Continue tamoxifen daily for 5 years 1EBCTCG, Lancet 2011;378:771-84 Davies et al., SABCS 2012; abstract S1-2

  39. ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis Median F/u = 8 years for compliance, recurrence, death Davies et al., SABCS 2012; abstract S1-2

  40. ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis • Breast cancer mortality: • 10 years of tamoxifen is estimated to reduce breast cancer mortality by one-third in the first decade and by one-half in the second decade *P = .0016 **P = .0001 ***P < .00001 Davies et al., SABCS 2012; abstract S1-2

  41. ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis • Mortality comparison: • The above chart shows that the risk of death caused by tamoxifen side effects is greatly outweighed by the benefit in the reduced risk of death from breast cancer provided by 10 years of tamoxifen therapy Davies et al., SABCS 2012; abstract S1-2

  42. Metastatic Breast Cancer

  43. CONFIRM: Effect of Fulvestrant 500 mg vs250 mg on Survival in Postmenopausal Women • Objective: • Compare fulvestrant 500 mg/month with 250 mg/month (approved dosing) for the treatment of postmenopausal women with ER-positive advanced breast cancer whose disease progressed after previous hormonal therapy • CONFIRM Phase III study design: (N = 735) • Fulvestrant 500 mg • Intramuscular injections on days 0, 14, 28, and every 28 days thereafter • Eligibility criteria: • Postmenopausal • Advanced ER-positive breast cancer • Disease progression during or after prior hormonal therapy RANDOMI ZE • Fulvestrant 250 mg • Intramuscular injections on days 0, 28, and every 28 days thereafter (with placebo injections on day 14) Primary endpoint: PFS Di Leo et al., SABCS 2012; abstract S1-4

  44. CONFIRM: Effect of Fulvestrant 500 mg vs250 mg on Survival in Postmenopausal Women • Baseline characteristics appeared well-balanced between treatment arms • Efficacy results: • Subsequent therapies were well-balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one-third receiving other hormonal therapy *P = .006 **P = .001 ***P = .016 †First analysis was performed at 50% maturity ‡ Final analysis was performed at 75% maturity Di Leo et al., SABCS 2012; abstract S1-4

  45. CONFIRM: Effect of Fulvestrant 500 mg vs250 mg on Survival in Postmenopausal Women • Safety results (reported during main trial + follow-up phase) : • A total of 11 SAEs led to death: Di Leo et al., SABCS 2012; abstract S1-4

  46. Phase III BOLERO-2 Trial:Exemestane +/- Everolimus in Advanced BC • N = 724 • Postmenopausal ER+ • Unresectable locally advanced or metastatic BC • Recurrence or progression after letrozole or anastrozole R EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) 2:1 Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases • Endpoints • Primary: PFS (local assessment) • Secondary: OS, ORR, QOL, safety, bone markers, PK Hortobagyi G et al. SABCS 2011 (Abstract #S3-7), Baselga, NEJM 2011

  47. BOLERO-2 Trial: Final Progression-Free Survival Analysis (18-month follow-up) • PFS impact consistent across all prospectively defined subgroups • Overall survival data still not mature (HR=0.77; 95% CI, 0.57-1.04) • Most common grade 3 or 4 AEs were stomatitis (8%), hyperglycemia (5%), and fatigue (4%) Swain et al., SABCS 2012; abstract P6-04-02

  48. LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced Breast Cancer • Rationale: • Clinical data suggest that downregulation of VEGF may overcome endocrine therapy resistance and improve efficacy to hormonal therapy1 • Endocrine therapy + bevacizumab has been shown to be safe and active in phase II testing2,3 • Objective: Determine whether bevacizumab can delay resistance to endocrine therapy in patients with HR-positive advanced breast cancer • LEA Phase III, open-label, multicenter study design: (N = 380) • Endocrine therapy • Letrozole 2.5 mg/d or • fulvestrant 250 mg q28d • Eligibility criteria: • Postmenopausal • Advanced HR-positive, HER2-negative breast cancer • No previous therapy for advanced disease RANDOMI ZE • Endocrine therapy + bevacizumab • Letrozole 2.5 mg/d or • fulvestrant 250 mg q28d + • bevacizumab 15 mg/kg q Primary endpoint: PFS 1Ryden et al. J ClinOncol. 2005;23:4695-704 2Forero-Torres et al. Clin Breast Cancer. 2010;10(4):275-80 3Traina et al. J ClinOncol, 2010;28(4):628-33 Martin et al., SABCS 2012; abstract S1-7

  49. LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced Breast Cancer • Results: • Baseline characteristics were well-balanced: • Approximately 80% had metastatic disease • Approximately 50% had received previous adjuvant hormonal therapy • Approximately 90% of patients received letrozole; the remainder received fulvestrant • Adverse events increased on the bevacizumab-containing arm included leukopenia and thrombocytopenia (P < .01); also fatigue, hypertension, hemorrhage, elevated liver enzymes, and proteinuria (P < .001). Martin et al., SABCS 2012; abstract S1-7

  50. TRIO-18: Addition of CDK Inhibitor PD 0332991 to Letrozole for Advanced Breast Cancer • Rationale: • PD 0332991 is an oral highly selective cyclin-dependent kinase (CDK) 4/6 inhibitor that prohibits cell cycle progression • It has been shown that PD 0332991 has synergistic activity in combination with hormonal therapy (tamoxifen)1 • A Phase I/II study of letrozole and PD 0332991 was initiated • The phase 1 portion has been completed and the dose of PD 0332991 selected • Phase II study design (N=99) • Eligibility criteria: • ER-positive, HER2-negative disease • Locally recurrent or metastatic • Previously untreated for advanced disease • CCND1 amplification and/or loss of p16 RANDOMI ZE PD 0332991 125 mg QD* + letrozole 2.5 mg QD *3 weeks on, 1 week off Letrozole 2.5 mg QD Primary endpoint: PFS 1Musgrove et al. Nat Rev Can. 2011;11:558-72 Finn et al., SABCS 2012; abstract S1-6

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