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Update on Breast Cancer: ASCO 2004

Update on Breast Cancer: ASCO 2004. Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast Oncology Clinical Trials Program University of California San Francisco Comprehensive Cancer Center. ASCO Update: Breast Cancer Chemotherapy. Neoadjuvant therapy

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Update on Breast Cancer: ASCO 2004

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  1. Update on Breast Cancer: ASCO 2004 Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast Oncology Clinical Trials Program University of California San Francisco Comprehensive Cancer Center

  2. ASCO Update: Breast Cancer Chemotherapy • Neoadjuvant therapy • Herceptin for HER2 positive disease • Adjuvant therapy • Dose dense therapy for high risk node positive disease • Metastatic disease • Weekly vs every three week paclitaxel • Gemcitabine plus paclitaxel vs paclitaxel • Novel cytotoxics • Abraxane • Targeted therapy/surrogate endpoints • Prognostic factors • Gene analysis • Circulating tumor cells

  3. ASCO Update: Breast Cancer Hormone Therapy • Risk of relapse at 5 years • Update on MA.17 • Effects of exemestane on bone and cardiovascular endpoints • Exemestane as first-line therapy for metastatic disease

  4. Neoadjuvant Chemotherapy for Breast Cancer in HER2 Positive BC • Trastuzumab improves survival when added to chemotherapy for MBC • Remarkable synergy exists when combined with doxorubicin • Limited by significant cardiac toxicity • Is there a way to capitalize on the benefits of both agents without increasing the risk of cardiac damage?

  5. Significantly Higher Pathological Complete Remission (PCR) Rate Following Neoadjuvant Therapy with Trastuzumab [Herceptin (H)], Paclitaxel (P) and Anthracycline-Containing Chemotherapy (CT): Initial Results of a Randomized Trial in Operable Breast Cancer (BC) with HER-2 Positive Disease • Objectives • Compare the pathologic complete response rate in patients receiving chemotherapy with or without trastuzumab • Histologically confirmed invasive breast cancer T 1-3, N 0-1, M0 • Her-2 + by FISH or IHC 3+ Buzdar et al, ASCO 2004

  6. Paclitaxel: 225 mg/m2 over 24 h FEC: 75mg/m2 epirubicin

  7. The addition of trastuzumab to taxane and anthracycline-containing chemotherapy as utilized in this trial significantly increased the pathological complete response rates in patients with HER-2 positive breast cancer • Addition of trastuzumab resulted in significantly higher incidence of neutropenia • 11 vs 21, p .03 • No clinical cardiac toxicity was observed • Where should we go from here? • Not a regimen to take home yet! • Consider use of Herceptin off protocol for LABC • Adjuvant data to follow……

  8. Dose Dense Sequential Chemotherapy with ETC: The AGO Trial. Mobus et al, #513 26.4% required transfusions in the phase I/II study of dose density

  9. Time to Relapse and RFS Subgroup Analysis • Time to relapse 127 vs 94 mo (p = .0009) • No impact on TTR of epoietin • Less transfusions • 28 v 12% • One patient died of AML in the ETC arm Hazard ratio 0.64

  10. Take Home Points • Dose dense and dose intense sequential ETC is better than standard EC followed by T in women with > 4 + axillary lymph nodes • This is the first large study to show survival benefit in patients with high risk node positive disease • Short follow-up (28 months) • Unclear whether benefits are due to the dose-density or the dose-intensity of the regimen • Superior arm had higher doses as well as higher density • Treatment is reasonably well tolerated with growth factor support • Chemotherapy can be given safely every 2 weeks, this shortens duration of treatment • Epo had no effect on survival • Contrary to prior studies suggesting worse outcome with epo

  11. CALGB 9840: Phase III study of weekly vs. every third week paclitaxel in the treatment of metastatic breast cancer, with trastuzumab for HER2 + MBC and randomized for trastuzumab for HER2 normal MBC • Primary objectives • Weekly (q1w) paclitaxel (P) improves response in MBC as compared to q3w P • Adding trastuzumab (T) to q1w or standard (q3w) P improves response for HER2 normal MBC • Secondary objective • TTP and OS are better with weekly paclitaxel compared with every three week dosing Seidman et al, ASCO 2004

  12. CALGB 9342To reduce patients required for study endpoints, and study costs, 158 patients were ‘borrowed’ (total 738) 250 mg/m2 210 mg/m2 175 mg/m2 Multivariate p = Response TTP OS 23% 26% 21% NS 3.9 mos 4.1 mos 4.9 mos 0.12 11 mos 12 mos 14 mos 0.30 Winer E et al. J Clin Oncol 22: 2061-2068, 2004

  13. CALGB 9840: Design MBC with 0-1 Prior Chemotherapy for MBC, > 12 mo Since Adjuvant Taxane 2000-2003 (n=406; HER2 known) H E R 2 (-) H E R 2 (+) q3wP+T q1wP+T 1998-2000 (n=171; HER2 unknown) q3w P q1w P = paclitaxel 80 mg/m2* qw vs 175 mg/m2 q 3w = trastuzumab 4mg/kg load, 2 mg/kg/w** *first 116 pts at 100 mg/m2 x 6, then all pts 80 mg/m2 qw **Her 2 + receive trastuzumab, Her 2 – randomized to T or no T

  14. CALGB 9840Tumor Response (all patients) (HER2 normal patients) (OR=1.61, p=0.017) (p=0.34) 100 80 60 40 20 0 40% 28% 35% 29% Percentage q1w P q3w P T No T n = 344 373 112 111

  15. CALGB 9840Time to Progression (Adjusted HR=1.45, p=0.0008) (p=0.09) 12 11 10 9 8 7 6 5 4 3 2 1 9 mos 5 mos 7 mos 6 mos (all patients) (HER2 normals) months q1w P q3w P T No T n (events/pts) = 221/350 324/385 74/113 82/115

  16. CALGB 9840: Conclusions • Weekly P is superior to every 3 week P for response and time to progression in MBC , there was no difference in overall survival (24 vs 16 mo) • Trastuzumab does not improve outcome when added to P for HER2 normal MBC • Companion correlative studies are pending • Less neutropenia in the weekly arm • 5 vs 15% grade 3-4 • More sensory neuropathy in the weekly arm • 30% - 100 mg weekly (n116); 19% - 80 mg weekly (n228) • 12% - q 3 weeks (n224) • Do the borrowed patients affect the observed outcome? • 75 v 20% second line • Without those patients, trend toward improved response, significant improvement in TTP

  17. Phase III Study of Gemcitabine plus Paclitaxel versus Paclitaxel as Frontline Therapy for MBC: Albain et al, ASCO 2004 Treat until documented PD All sites of disease assessed every 8 weeks GT arm(21-day cycle) R A N D O M I Z E Day 1: Paclitaxel 175 mg/m2 (3 hr) Gemcitabine 1250 mg/m2 Day 8: Gemcitabine 1250 mg/m2 ELIGIBILITY Unresectable, locally recurrent or metastatic measurable disease No prior chemotherapy for advanced disease Prior adjuvant chemotherapy (anthracycline-based, unless contraindicated) T arm (21-day cycle) Day 1: Paclitaxel 175 mg/m2 (3 hr) Standard paclitaxel premedications 98 centers, 19 countries

  18. JHQG Planned Interim Analysis Endpoint GT T p-value Response rate 40.8% 22.1% <0.0001 (HR 0.65) Median TTP 5.2 2.9 <0.0001 6-month 37% 23% 0.0027 progression-free Deaths 160 183 Censored 40.1% 30.2% Median OS, mos 18.5 15.8 12-month survival 70.7% 60.9% 18-month survival 50.7% 41.9%

  19. 1.0 0.8 GT 0.6 Overall Survival Probability 0.4 T 0.2 0.0 0 6 12 18 24 30 36 42 Overall Survival Time (Months) JHQG Interim Overall Survival

  20. JHQG Subsequent Chemotherapy* Treatment Post-study GT T Total 44.2% 49.2% Number of regimens 1 – 2 29.5% 35.1% 3 14.6% 14.1% Regimens or single agent Vinorelbine 24.7% 27.9% Capecitabine 17.6% 14.9% Docetaxel 10.5% 10.3% Gemcitabine 3.8% 14.1% *At time of interim data lock

  21. Conclusions • Gemcitabine/paclitaxel doublet joins capecitabine/docetaxel and trastuzumab/taxane in providing superior outcomes to taxane monotherapy • GT is very well-tolerated, and thus can be studied in the adjuvant setting • The major difference in toxicity is hematologic • 48 vs 11% grade 3-4 neutropenia • 10 vs 4 RBC transfusions • Two ongoing trials (Tango, NSABP), neoadjuvant planned (NSABP) • The risk-benefit profile favors GT and offers a new option for frontline treatment in women with MBC

  22. Enhanced TumorCell (C) High uptake by tumors Tumor Cell ABRAXANE Transport From Blood Circulation, through Endothelial Cells and into TUMORS Leaky junction Tumor Interstitium (A) Enhanced Penetration & Retention of nab particles and macromolecules Lumen of Tumor microvessel Albumin-receptor (gp60, albondin) Endothelial Cell Caveolae (vesicles) (B) Receptor-mediated Transcytosis

  23. Phase II Weekly ABI-007 (Abraxane) in Taxane Refractory MBC. Blum et al Evaluable Patients, n (%) 106 (100%) Objective Partial Response(PR) 16 (15%) 95% CI 8.3% - 21.9% Disease Control(PR+SD  16 weeks) 32 (30%)95% CI 21.4% - 38.9% Objective Disease Tumor Growth After: n RR Control Taxotere alone 33 24% 35% Taxol alone 31 16% 37% Both 28 7% 27%

  24. Conclusions • Long-term disease control was achieved with a well tolerated weekly regimen of Abraxane • ABI-007 (100 mg/m2 weekly) compares favorably to reported data 1,2 using weekly Taxol 80 mg/m2 • G-4 neutropenia (1% vs 5%) • G-3 neuropathy (4% vs 23% sensory, 0% vs 8% motor respectively) • In light of the very low incidence of grade 3 or 4 toxicities, further studies of ABI-007 are focusing on neoadjuvant and adjuvant breast cancer, higher weekly doses (125 and 150 mg/m2), and combinations with other drugs • Perez EA, Vogel CL, Irwin DH, Kirshner JL, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19:4216-23, 2001 • Seidman, ASCO 2004

  25. Role for Bisphosphonates in the Treatment of Breast Cancer • 3 trials on the use of clodronate (1600 mg/day) in breast cancer pts • Finnish study (N = 282): DECREASED disease-free survival • 10-year follow-up • Primary node-positive breast cancer • German study (N = 290): PROLONGED overall survival • 8.5-year follow-up • Primary breast cancer with micrometastases to bone marrow • English study (N = 1069): IMPROVED survival; ↓ bone metastases • 5-year follow-up • Primary operable stage 1-3 breast cancer • NSABP trial will help to clarify role of clodronate in the treatment of breast cancer • Intergroup trial to open soon 1. Saarto T, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 527. 2. Jaschke A, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 529. 3. Powles T, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 528.

  26. ASCO 2004 #522 Verification of Adjuvant! on an Independent Data Set • Adjuvant! is a Web-based computer model based on clinical trial data • Predicts 10 year DFS and OS based on • Age • Tumor size, #LN • ER/PR status • Hormonal and chemotherapy administered • Continually updated (last revision 8/04) • Clinical and treatment data obtained from British Columbia cancer registry • 4083 women treated from 1989-1993 • T1-2N0-1 BCa, 66% T1, 34% N1, 58% ER(+) • No tx 45%, tam 30%, chemo 16%, T +CT 9% • Data entered into adjuvant and compared to observed 10 year DFS and OS Olivetto et al.

  27. ASCO 2004 #522Verification of Adjuvant! on an Independent Data Set • Adjuvant! Predicted overall DFS and OS within 1% of observed: • For OS (71.7% pred, 72% obs) • For DFS (71% pred, 70.1% obs) • Adjuvant was overly optimistic in: • DFS in women <35 years (pred 67%, obs 54%, p<0.002) • DFS in women on CT (pred 65%, obs 61%, p=0.056) • DFS in women on CT + tam (pred 68%, obs 61.7%, p=0.012) • Conclusion: • Adjuvant! Works reliably well in large test dataset, likely useful for clinical practice • Caution in interpreting benefit of CT and CT + tam • ‘Toggle’ switch allows increase or decrease in risk based on known additional risk factors (e.g. HER2, LVI, age)

  28. Neoadjuvant Therapy: Prediction of pCR using Genomics • Background: Pathologic eradication of invasive breast cancer (pCR) is an independent predictor of outcome (DFS and OS) in women undergoing primary chemotherapy Can genes be identified whose expression correlates with the likelihood of pCR to primary chemotherapy (doxorubicin and paclitaxel)? • 89 evaluable patients • 11 patients with pathologic complete response (pCR) • 4 pts ER+ by IHC • pCR rate in ER+ pts = 8% (95% CI, 1%, 15%) • 7 pts ER- by IHC • pCR rate in ER- pts = 23% (95% CI, 8%, 37%) • Overall, pCR rate = 12% Gianni et al, ASCO 2004

  29. Results - Univariate analysis of Gene Expression and pCR • 86 genes correlated with likelihood of pCR (p < 0.05; unadjusted) • 30 genes correlated p < 0.01 • 18 genes correlated p < 0.005 • 2 genes correlated p < 0.0001 • 20 genes would have been expected by chance alone (p < 0.05) • Higher likelihood of pCR associated with: • HIGHER expression of PROLIFERATION genes CDC20, MYBL2, FBXO5, MCM2, MCM6, CDC25B • HIGHER expression of IMMUNE-RELATED genes MCP1, CD68, CTSB, CD18, ILT, CD3z, FasL, HLA.DPB1 • LOWER expression of ESTROGEN-RELATED genes PR, SCUBE2 (CEGP1), ER, NPD009, GATA3, IGF1R, IRS1 Gianni et al, ASCO 2004

  30. Validation Set n=75 <5 CTC(n=34) ≥5 CTC(n=41) ~6.7 mos ~2.4 mos Cox Hazards Ratio=1.8103 Logrank p=0.0360 (p value=0.04) CTC at 1st Follow-up predict PFS Detection of Circulating Tumor Cells Predicts Rapid Progression in Metastatic Breast Cancer:Results of a Prospective Clinical Trial: Hayes et al 1st Follow-up (3 - 4 wk) N = 163 Logrank p < 0.0001 100% 90% 80% 70% <5 CTC (n=114) ≥5 CTC (n=49) 60% ~7-8 mos 50% ~5-6 WEEKS %Probability of Progression Free Survival 40% 30% 20% 10% 0% 0 10 20 35 40 45 50 55 60 65 70 75 5 15 25 30 80 Time from Baseline (Weeks) Baseline CTC predict PFS

  31. Conclusions In metastatic Breast Cancer: • Baseline CTC • 50% of patients ≥ 5CTC • Independent prognostic indicators of favorable & unfavorable outcomes (PFS and OS) • 1st Follow-up CTC • 30% of patients ≥ 5CTC • When elevated, predict short PFS and OS and may indicate patient is on a futile therapy • Do these data apply to all patients? • All patients had measurable disease • Data appear less robust for patients on endocrine therapy • Ongoing or planned clinical trials: • Accruing patients with non-measurable disease • A prospective randomized trial is being designed to determine if changing therapy at 3-4 weeks improves outcomes

  32. What Happens to Patients with Early Stage Breast Cancer after Five Years?#585: Hortobagyi et al • Goal • To determine the magnitude of residual risk of recurrence 5 years after diagnosis of breast cancer • 1511 patients treated between 4/74 and 7/98with anthracycline and endocrine therapy as indicated were relapse free at 5 years • Median follow-up 74 months • Majority were stage II, 50% ER+

  33. Conclusions • Patients with breast cancer still have substantial residual risk of relapse 5 years after diagnosis • Stage II • 13% for the next 5 years • 21% for the next 10 years • Stage III • 18% for the next 5 years • 30% for the next 10 years • Stage I remains to be defined • Residual risk is higher for patients with HR+ disease than those with HR- disease • Extended endocrine therapy may further reduce risk of recurrence or death for patients with HR+ disease • Additional and more effective therapy is needed for patients with HR- breast cancer

  34. NCIC CTG Intergroup Trial MA.17 Design Goss PE et al., ASCO 2004 and N Engl J Med 2003;349 All Patients Disease-free Letrozole 0 – 3 months n = 2575 Tamoxifen Placebo n = 2582 4.5 - 6 years initial adjuvant 5 years extended adjuvant Stratification:Receptors +ve / unknown Lymph Node + ve, - ve, unknown Adjuvant Chemo Y / N

  35. Interim Analysis DFS events: 207 Deaths: 73 # pts at 40 months = 384 Median follow-up: 2.4yrs Final Analysis DFS events: 247 Deaths: 113 # pts at 40 months = 1115 Median follow-up: 2.5yrs MA17 Final Analysis Toxicity - Efficacy 2003 March Aug Oct 1998 2003 2004

  36. Total Recurrences of Breast Cancer 155 Node + Node - 102 92 63 50 23

  37. Summary of Key Endpoints in Nodal Subgroups HR=1.52 (0.76-3.06) HR=0.45 (0.27-0.75) HR=0.63 (0.31-1.27) Node* -ve Node -ve Node -ve Distant* DFS DFS* OS Node* +ve Node* +ve Node* +ve HR=0.61 (0.45-0.84) HR=0.61 (0.38-0.98) HR=0.53 (0.36-0.78) * = Statistically significant

  38. MA.17: Incidence of Adverse Events (All Grades) Letrozole (%) Placebo (%) P value Hot Flashes 58 54 0.003 Arthritis/Arthralgia 25 21 < 0.0001 Muscle pain 15 12 0.04 Vaginal bleeding 6 8 0.005 Hypercholesterolemia 16 16 0.79 Cardiovascular Events 6 6 0.76 Osteoporosis 8 6 0.003 Bone fractures 5.3 4.6 0.25 Discontinuations due to adverse events 5 4 0.02 Discontinuations for other reasons 4 5 0.1 90% of AE’s Grade 1 or 2

  39. A Randomized Placebo Controlled Feasibility Study of Exemestane vs Placebo in Postmenopausal Women with Early Breast Cancer at Low Risk. #518: Lonning et al • Exemestane moderately increases bone loss in the lumbar spine and the femoral neck. • 0.10 reduction in bone mineral density femoral T-score on exemestane • Corresponds to an increase in the lifetime hazard rate of fracture of < 1.15 (Cummings et al. JAMA 2002; 288: 1889-97). • No patient with normal bone mineral density at baseline became osteoporotic on either treatment. • The frequency of fractures did not different between exemestane and placebo. • Bone loss was higher than expected in the placebo arm • At 25 mg a day, exemestane does not appear to prevent bone mineral density loss in this patient population

  40. Summary of First Line Hormonal Treatment for MBC with Exemestane or Tamoxifen in PM Women: The EORTC Randomized Phase III Trial Anastrozole Anastrozole Letrozole Exemestane Patients, N 170 vs 182 340 vs 328 453 vs 454 182 vs 189 OR, % 21 vs 17 33 vs 33 30 vs 20* 46 vs 31* Clin. Benefit, % 59 vs 46* 56 vs 56 49 vs 38* 66 vs 49* Med. PFS, mo 11 vs 6*8 vs 8 9 vs 6* 10 vs 6* ER unknown, % 11 vs 11 56 vs 54 34 vs 33 15 vs 11 Significantly different from Tamoxifen (*) Nabholtz et al. J Clin Oncol. 2000;18:3758-3767; Bonneterre et al. J Clin Oncol. 2000;18:3748-3757; Mouridsen et al. J Clin Oncol. 2001;19:2596-2606; Mouridsen et al. Breast Cancer Res Treat. 2001;69:211, abst 9; Paridaens et al, #515

  41. Conclusions • New combinations, targeted biologic agents, and new treatment schedules are improving options for treatment and outcome for women with high risk and advanced breast cancer. • The GT combination will be compared to XT in the planned new NSABP neoadjuvant trial • Herceptin adjuvant trials are ongoing, neoadjuvant trials are planned • Genomics and CTCs may help to determine appropriate individual therapy in the future • Aromatase inhibitors have an established efficacy in the treatment of early stage, hormone receptor positive breast cancer • MA.17 in node positive breast cancer is the first adjuvant AI trial to show improvement in survival • We need the data from BIG Femta to understand sequence • Understanding duration is more of a challenge.

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