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Metastatic Breast Cancer New Therapeutic Strategies

Medical Approach . Agressive versus indolent diseaseVisceral versus bone/soft tissuesHormone sensitive versus insensitiveHER-2 positive versus negative diseaseGood PS versus Poor PSComorbidities versus not. Treatment Selection Criteria. HER-2 expressionER/PR expressionSites of metastasesMeno

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Metastatic Breast Cancer New Therapeutic Strategies

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    1. Metastatic Breast Cancer New Therapeutic Strategies Prof. Gilberto Schwartsmann Hospital de Clínicas de Porto Alegre Universidade Federal do Rio Grande do Sul

    2. Medical Approach Agressive versus indolent disease Visceral versus bone/soft tissues Hormone sensitive versus insensitive HER-2 positive versus negative disease Good PS versus Poor PS Comorbidities versus not

    3. Treatment Selection Criteria HER-2 expression ER/PR expression Sites of metastases Menopausal status Performance status Disease-free interval Prior therapy Concomitant diseases Patient preferences

    4. Current Treatment Strategies for Women with Predominant Visceral Metastases & Clinically Agressive Disease HER-2 + / HR -: CT + herceptin HER-2 + / HR +: CT+ herceptin: then herceptin+HT HER-2 - / HR +: CT alone: then HT HER-2 - / HR -: CT intensive + avastin?

    5. Common Regimens for Patients HER-2 + / HR - Herceptin / paclitaxel +/- carboplatin Herceptin / docetaxel +/- carboplatin

    6. Common Regimens for Patients HER-2 + / HR + Herceptin / paclitaxel +/- carboplatin Herceptin / docetaxel +/- carboplatin Maintenance with Herceptin / HT

    7. Common Regimens for Patients HER-2 - / HR + No prior adjuvant anthracycline or up to 12m: AC, EC, FAC, FEC, paclitaxel or docetaxel Prior adjuvant anthracycline: paclitaxel, docetaxel/capecitabine, docetaxel/gemcitabine Prior adjuvant anthracicline/taxane and relapse up to 12 m: capecitabine, vinorelbine or gemcitabine When possible, add avastin Maintenance with HT

    8. Common Regimens for Patients HER-2 - / HR - No prior adjuvant anthracycline or up to 12m: AC, EC, FAC, FEC, paclitaxel or docetaxel Prior adjuvant anthracycline: paclitaxel, docetaxel/capecitabine, docetaxel/gemcitabine Prior adjuvant anthracicline/taxane and relapse up to 12 m: capecitabine, vinorelbine or gemcitabine When possible, add avastin

    9. Current Treatment Strategies for Women with Predominant Skeletal / Soft-Tissue Metastases & Clinically Indolent Disease HER-2 + / HR -: CT + herceptin HER-2 + / HR +: CT+ herceptin: then herceptin+HT HER-2 - / HR +: CT alone: then HT HER-2 - / HR -: CT intensive + avastin?

    10. Common Regimens for Patients HER-2 + / HR - Herceptin / paclitaxel +/- carboplatin Herceptin / docetaxel +/- carboplatin

    11. Common Regimens for Patients HER-2 + / HR + Herceptin / HT Lapatinibe / HT CT / Herceptin / HT

    12. Common Regimens for Patients HER-2 - / HR + HT alone for pre-M: tamoxifen / goserelin HT isolada for post-M: anastrazole, letrozole, examestane, fulvestrane

    13. Common Regimens for Patients HER-2 - / HR - Single agents or combinations in sequence: paclitaxel, docetaxel, doxorubicin, capecitabine, vinorelbine, gemcitabine, AC, EC, FAC, FEC. If possible, add avastin

    14. Second-line Regimens for HER-2 Positive Patients Replace herceptin for lapatinibe or combine them or with capecitabine Capecitabine, vinorelbine, gemcitabine, cisplatin, AC, EC, FAC, FEC. If possible, add avastin

    15. Second-line Regimens for HER-2 Negative Patients Refraactory to anthracyclines: paclitaxel, docetaxel, capecitabine, vinorelbine, gemcitabine, cisplatin. If possible, avastin

    16. Second-line Regimens for HER-2 Negative, Antracicline/Taxane Resistant Patients Capecitabine, vinorelbine, gemcitabine, cisplatin, carboplatin, irinotecan, ixabepilone.

    17. HER-2 & Breast Cancer HER-2 oncogene or its protein receptor HER-2 is overexpressed in 25-30% of breast cancers HER-2 overexpression is a poor prognostic factor 1/3 of HER-2 positive patients respond to trastuzumab 2/3 of HER-2 positive patients respond to taxane plus trastuzumab combinations

    18. HER-2 & Breast Cancer Although trastuzumab reduces HER-2 mediated signalling, it does not reduce signalling from other HER receptors The heterodimer HER-2/HER-3 activates PI3K pathway and prevents trastuzumab growth inhibition HER-3 high protein levels predicts for poor response to trastuzumab

    19. Lapatinib Oral small molecule Dual inhibitor of tyrosine kinase activity of HER-2 and EGFR Active in HER-2 resistant breast cancers Positive trials in combinations with capecitabine and with trastuzumab, in patients failing to trastuzumab

    20. TRIPLE-NEGATIVE BREAST CANCERS These subtypes are usually basal-like Harboring DNA-damage repair defects Could be suitable to therapeutic interventions with PARP-1 inhibitors Preliminary data showing single agent activity, as well as significant effects in combination with platinum/gemcitabine

    21. Triple-Negative These tumors are clinically agressive and with worse prognosis They do not possess the classical targets, such as ER or HER-2 Triple-negative tumors could be more sensitive to PARP-1, DNA damaging, EGFR and angiogenesis inhibitors

    22. ANTHRACYCLINES Topo II gene amplifications/deletions and topo II protein overexpression seem to predict response to topo II inhibitors HER-2 amplified tumors have concomitant topo II aberrations in 50% of cases The majority of hyperproliferative tumors carry topo II protein overexpression Anthracycline activity correlates with topo II gene aberrations and protein overexpression

    23. TAXANES Microtubule-associated parameters such as TAU protein, HER-2 gene amplification and p53 gene mutations are potential markers of taxane sensitivity Tubulin mutations are related to resistance to taxanes in animal and human tumors

    24. DNA-damaging agents BRCA1 protein seems to play a major role in activating DNA repair mechanisms Loss of function BRCA1 mutations might lead to a substantial deficit in DNA repair mechanisms, relying in other pathways That could translate into increased tumor sensitivity to alkylating agents and platinum.

    25. T-DM1 Trastuzumab/maytansine derivative DM1 (microtubule inhibitor) immunoconjugate Phase II in 60 patients failing to lapatinib showed RR of 39% (23/60 patients) It means that HER-2 is still a target for patients overexpressing HER-2, even after failure to trastuzumab Burris et al, JCO, 2009

    26. AZD2281 (0laparib) PARP inhibitor Oral administration Phase II in BRCA1-2 mutated patients showed RR in 38% of cases (9/24) A significant proportion of BRCA1-2 mutated cases share common features with triple-negative patients Tutt et al, JCO, 2009

    27. PATUPILONE Epothylone derivative Enters blood-brain barrier RR in patients with SNC disease who failed RT Phase II RR in 19% and 29% stable disease Conlin et al, JCO, 2008

    28. BSI-201 PARP inhibitor IV administration Phase II randomised trial of carboplatin and gemcitabine +/- BSI-201 in 116 patients showed advantage in RR (48% vs 16%) and DFS (6.9m vs 3.3m) O´Shaughnessy et al, JCO, 2009

    29. XL147 & SF1126 PI3K inhibitors Ongoing Phase I-II trials Responses in platinum-resistant patients Potentiates taxanes and platinum in experimental models RR in triple-negative patients

    30. Molecular Profile & Therapy ER/PR positive ER/PR negative HER-2 positive HER-2 negative Triple negative Directed to molecular pathways

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