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Highlights in the Management of Breast Cancer Rome, May 25-26, 2007

Highlights in the Management of Breast Cancer Rome, May 25-26, 2007. CLINICAL CASE. Dott.ssa Marinella Zilli Cattedra di Oncologia Medica Università “G. D’Annunzio” Chieti-Pescara Direttore: Prof. Stefano Iacobelli. Jan 2006: Right breast lumpectomy + axillary lymph node dissection.

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Highlights in the Management of Breast Cancer Rome, May 25-26, 2007

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  1. Highlights in the Management of Breast Cancer Rome, May 25-26, 2007 CLINICAL CASE Dott.ssa Marinella Zilli Cattedra di Oncologia Medica Università “G. D’Annunzio” Chieti-Pescara Direttore: Prof. Stefano Iacobelli

  2. Jan 2006: Right breast lumpectomy + axillary lymph node dissection Invasive Ductal Carcinoma, G3 pT2 (2.5 cm) pN2 (4/17) M0 ER 0% PR 0% HER2 +++ Feb 2006:Adjuvant treatment was started: ECx4 Docetaxel-Trastuzumab x 4 37-year-old premenopausalwoman Jul 2006:Ptstops cht and continues adjuvant trastuzumab. She receives also XRT in the right breast

  3. Dec 2006Intensive abdominal pain with AST, ALT, GT and increase of CA 15.3 ABDOMEN CT: MULTIPLE LIVER METASTASES Brain CT: Neg. Torax CT: Neg. Bone scan: Neg. This is an aggressive disease (Symptomatic, rapid evolution, time to recurrence < 1 year, unfavourable biology, important tumor burden)

  4. THERAPEUTIC AIM • Rapid tumor shrinkage • - to improve clinical symptoms • - to prolong survival

  5. Survival curves: overall and according to response

  6. Discussion points: 1. Continue Trastuzumab (T)? YES NO

  7. 2. Trastuzumab + Bevacizumab (B) + cht: a possible option? YES NO

  8. 3. Which chemotherapy? - Paclitaxel - Paclitaxel + Carboplatin - Paclitaxel + Gemcitabine - Vinorelbine - Vinorelbine + Gemcitabine - Vinorelbine + Carboplatin - Carboplatin + Gemcitabine - Capecitabine ?

  9. 1. Continue Trastuzumab (T)?

  10. Preclinical data support continuation of trastuzumab beyond disease progression Addition of trastuzumab to paclitaxel in the human breast cancer xenograft model KPL-4 progressing on trastuzumab monotherapy was shown to potentiate the antitumor activity of paclitaxel Fujimoto-Ouchi K et al, Proc Am Assoc Cancer Res 2005

  11. Retrospective analyses In patients with HER2+ advanced breast cancer progressing on trastuzumab-containing therapy, continuing trastuzumab alone or combined with other chemotherapy is feasible and safe, with encouraging tumor response and survival data. Tripathy D et al, J Clin Oncol 2004 Mackey J et al, Proc Am Soc Clin Oncol 2002 Fountzilas G et al, Clin Breast Cancer 2003 Bartsch R et al, BMC Cancer 2006 Garcìa-Sàenz JA et al, Clin Breast Cancer 2005 Stemmler HJ et al, Onkologie 2005

  12. Objective response rates and TTP were maintained in pts receveing two or more trastuzumab-based regimens The decline in ORR from 42.6% (in first line) to 30% (in beyond second line) compares to the expected drop of ORR with every further line of cht or ET in palliative treatment. No case of symptomatic CHF was observed Bartsch R et al, BMC Cancer 2006

  13. Favourable effect of Trastuzumab treatment in metastatic breast cancer patients: results from the French Hermine cohort study …continuing treatment with multiple lines of trastuzumab offered significant survival benefit Extra JM et al, SABCS 2006

  14. HOWEVER… In these retrospective studies, it is not possible to discern whether the observed benefits are derived from cht alone or whether the continuation of trastuzumab have significantly contribued to the therapeutic results. Phase III randomized trials are now ongoing to investigate this issue (three studies) GBG 26: Therapy Beyond Progression (TBP) study Pts with MBC HER2+ and progression during trastuzumab therapy Capecitabine (2500 mg/mq, d1-14 q21) R Capecitabine (2500 mg/mq, d1-14 q21) + Trastzumab (6 mg/kg d1 q21) Randomized phase III trial

  15. If tumor cells are able to switch from the HER2 to EGFR or other signal transduction pathways (VEGF, IGF1R), a continued treatment would not necessarily lead to a benefit. On the other hand, if no complete resistance develops, a discontinuation of trastuzumab might be cause a massive overshoot in tumor growth Ritter CA et al, Int J Pharmacol Ther 2004

  16. 2. Trastuzumab + Bevacizumab (B) + chemotherapy: a possible option?

  17. HER2 overexpressing human breast cancer xenografts exhibit increased angiogenic potential mediated by VEGF HER2-negative HER2-positive HER2 overexpressing breast cancer cells exibited increased angiogenesis in vivo compared to control cells Epstein et al, Breast Cancer Res Treat 2002, abs 570

  18. Overexpression of both HER2 and VEGF decreases survival in breast cancer 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0 Log-rank p=0.0133 HER2/VEGF –/– HER2/VEGF +/– Cumulative survival HER2/VEGF –/+ HER2/VEGF +/+ 0 20 40 60 80 100 120 Months Konecny, et al. Clin Cancer Res 2004

  19. The positive association between HER2 and VEGF expression, and their combined effect on clinical outcome support the strategy of targeting both VEGF and HER2 in breast cancer pts with HER2+ tumors…

  20. In preclinical xenograft models, superior efficacy is observed when T is given in combination with B T and B inhibit growth of MCF7/HER2 xenograft in vivo 800 700 Vehicle control 600 Tumor Volume (mm3) 500 Trastuzumab 400 300 Bevacizumab * 200 Trastuzumab + Bevacizumab 100 0 0 7 14 22 29 35 Treatment Day *p<0.05 compared to vehicle control and Trastuzumab-treated groups Pegram, Breast Cancer Res Treat 2004, abs 3039

  21. Phase I dose escalation of Trastuzumab + Bevacizumab in metastatic Breast Cancer COHORT 1 (N=3) Trastuzumab qw + bevacizumab 3 mg/kg day 7 then q2w COHORT 2 (N=3) Trastuzumab qw + bevacizumab 5 mg/kg day 7 then q2w HER2-positive (by FISH) recurrent or mBC n= 9 COHORT 3 (N=3) Trastuzumab qw + bevacizumab 10 mg/kg day 7 then q2w • No PK interaction between T and B • Clinical Response: 2 CR, 3 PR, 2 SD >6 mos; well tolerated; no DLT • Phase II (N=50) has begun, with bevacizumab 10 mg/kg, in first-line MBC Pegram, Breast Cancer Res Treat 2004, abs 3039

  22. Phase II combined biological therapy targeting HER2 and VEGF using Trastuzumab [T] and Bevacizumab [B] as first line treatment of HER2-amplified breast cancer HER2+ untreated MBC. No prior T or B treatment. 42/50 pts currently enrolled • STUDY OBJECTIVES • Clinical efficacy of T + B • Safety profile of T + B CARDIAC ADVERSE EVENTS (NCI-CTC V.2) G1 G2 G3 G4 7 pts 5 pts 0 pts 1 pt Pegram et al, SABCS 2006, abs 301

  23. INTERIM EFFICACY DATA Response (37 evaluable pts) CR PR SD PD 1 19 11 6 N of pts 2.7 51.4 29.7 16.2 Percent OVERALL RESPONSE RATE: 54.1% B in combination with T is clinically feasible and active in HER2 amplified MBC, supporting the use of combination therapies against HER2 and VEGF for treatment of BC with HER2 alteration Pegram et al, SABCS 2006, abs 301

  24. 3. Which chemotherapy? - Paclitaxel - Paclitaxel + Carboplatin - Paclitaxel + Gemcitabine - Vinorelbine - Vinorelbine + Gemcitabine - Vinorelbine + Carboplatin - Carboplatin + Gemcitabine - Capecitabine

  25. Which chemotherapy in anthracycline- and taxane-resistant patients? No standard of care exists after failure of both anthracycline and taxane treatment. The most common treatments are chosen in view of their manageable toxicity profiles and reasonable efficacy, because no randomized study has so far demonstrated a benefit in OS after second-line cht MBC Capecitabine Vinorelbine Gemcitabine Valero V, JCO 1998 Blum JL, JCO 1999 Valerio MR, ASCO 2001 Livingston RB, JCO 1997 Gralow JR, Breast Cancer Res Treat 2005

  26. Dec 2006: Vinorelbine (25 mg/mq) Gemcitabine (1000 mg/mq) (d1, 8 q21) + Trastuzumab (6 mg/kg) (d1 q21) + Bevacizumab (15 mg/kg) (d1 q21) Jan 2007: CT scan  PR (after 4 cycles) May 2007: CT scan  SD (after other 4 cycles) We decided to treat our patient according to a non-standard but promising regimen combining chemotherapy with targeted therapy: Discontinued chemoterapy and continued T + B

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