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ABC1 - F. Cardoso - HER-2+ advanced breast cancer - State-of-the-art management of HER-2+ disease
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ABC1 - F. Cardoso - HER-2+ advanced breast cancer - State-of-the-art management of HER-2+ disease

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    ABC1 - F. Cardoso - HER-2+ advanced breast cancer - State-of-the-art management of HER-2+ disease ABC1 - F. Cardoso - HER-2+ advanced breast cancer - State-of-the-art management of HER-2+ disease Presentation Transcript

    • State-of-the-art management of HER-2+ disease Fatima Cardoso, MD ESO Breast Cancer Program CoordinatorDirector Breast Cancer Unit & Breast Cancer Research Program Champalimaud Cancer Center Lisbon, Portugal
    • IMPORTANT LESSONS FROM HER-2 + MBC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on •Several possible combinations with cytotoxic and endocrine agents•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • SHOULD WE BIOPSY METASTASES & REPEAT ER/PR/HER-2? Current recommendation: WHENEVER POSSIBLE A BIOPSY OF THE METASTATIC LESION SHOULD BE PERFORMED • WHY? • BUT…
    • ASCO 2010: Significant Rate of Discordancy Between Primary and Metastases #1007 #CRA 1008 #1009 Studies Amir et al. Locatelli et al. Karlsson et al. N = 271 N = 255 N = 477 prospective retrospective (liver) retrospectiveER+ primary with loss in 21/174 (12%) 22/197 (11%) 123/336 (36%)recurrenceER- primary with gain in 8/57 (14%) 15/58 (25%) 32/141 (22%)recurrenceOverall ER discordance rate 12% 14.5% 32%Overall PR discordance rate 34% 48% 43%HER2- primary with gain in 9/197 (4.6%) 7/118 (5.9%) n.d.recurrenceHER2+ primary with loss in 3/24 (12.5%) 17/54 (31.5%) n.d.recurrenceChange in management from 15% 12% n.d.results of recurrence biopsyRichardson AL. Presented at: 2010 ASCO Annual Meeting; 4-8 June 2010: Chicago, Illinois, United States.
    • % « FALSE » RESULTS: IHC & FISH• European central vs local lab in the ALTTO trial: • ER 21 % • PgR 22 % • HER2 19 % IHC & 12 % FISH• US central vs local lab in the ALTTO trial: • ER 8 % • PgR 13 % • HER2 26 % IHC & 25 % FISH Courtesy G. Viale
    • META-ANALYSIS OF DISCORDANCE BETWEEN PRIMARY VS. METS: HER-2 STATUSHoussami et al, Breast Cancer Res Treat, 2011, DOI 10.1007/s10549-011-1632-x
    • META-ANALYSIS OF DISCORDANCE BETWEEN PRIMARYHoussami et al, Breast Cancer Res Treat, 2011 VS. METS: HER-2 STATUS • The pooled proportion of HER2 discordance was modest (5.5%; 3.6–8.5%) • Significant association between HER2 discordance and the type of metastasis (distant metastases showed higher proportions of HER2 discordance (9.6%; 4.9–17.7%) than LN mets only (4.2%; 2.5–7.1%)) • Weak evidence (P = 0.074) discordance “primary HER2-neg” to “paired mets HER-2+” more likely than the reverse• Limitations: meta-analysis of published studies (heterogeneity), nobreakdown by exact site of distant metastasis (bone mets issue!)• Strenghts: Looked very carefully at all covariates, all studies(re)tested primary & mets at same time. If only due to technicalissues no consistent pattern should be seen!
    • AGAINST REBIOPSY IN FAVOR OF REBIOPSY• No level 1 evidence • It is reasonable if it may – No prospective study with influence treatment decision survival gain – Old cases/from other – Some prospective studies institution(s) ongoing (but not with • It is a balance benefits/risks survival as primary – Difficulty: Lymph nodes vs. endpoint) bone or liver• There is a risk for – Accuracy: Soft tissue vs. misinterpretations bone• In many countries, it is not covered
    • SHOULD WE BIOPSY METASTASES & REPEAT ER/PR/HER2? REASSESS BIOLOGY AT TIME OF RECURRENCE … but…• Does the tumor biology change overtime?• How is it influenced by the different therapies given? • Neoadjuvant trials have shown important differences in pre and post treatment biomarker status • Emergency of resistance is a proof that biology changes ONGOING EVALUATION OF DISEASE STATUS & BIOLOGY
    • IMPORTANT LESSONS FROM HER-2 + MBC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on •Several possible combinations with cytotoxic and endocrine agents•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • IMPORTANCE OF EARLY ADMINISTRATION M77001 trial: estimated survival Trastuzumab + docetaxel (n=92) Docetaxel alone/crossover (n=41) 1.0 Docetaxel alone (n=53) 0.8 Estimated probability 0.6 0.4 0.2 15.3 21.9 27.7 0 0 3 6 9 12 15 18 21 24 27 30 MonthsMarty M et al. JCO 2005;23:4265–74
    • TAnDEM Study: Randomized, Open-Label Trial of Anastrozole ± Trastuzumab in Advanced HER2+, HR+ Breast Cancer Anastrozole Anastrozole + N = 207 Trastuzumab Median age 55 years Visceral disease 1/3 Prior chemo 1/2 Cross-over 70% 6.8% Response rate 20.3% P = .018 2.4 m Median PFS 4.8 m HR = 0.63; P = .0016 23.9 m Median OS 28.5 m P = .325 28.6 m Median OS 34.1 m for patients with centrally P = .451 confirmed HR status Trastuzumab added to anastrozole  RR, PFS, TTP and CBR Mackey JR, et al. Breast Cancer Res Treat. 2006;100(Suppl 1): Abstract 3. Kaufman B, et al. J Clin Oncol. 2009 Sept 28. [Epub ahead of print].
    • IMPORTANT LESSONS FROM HER-2 + MBC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on •Several possible combinations with cytotoxic and endocrine agents•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • HERNATA Study Design and Treatment Docetaxel 100 mg/m2 day 1 + Trastuzumab (8) 6 mg/kg day 1 R HER2+ Q 3 weeks* A M1 - LABC N Naϊve to CT Dexcept adjuvant O M Vinorelbine 30-35** mg/m2 days 1+8 I + Trastuzumab (8) 6 mg/kg day 1 Z E Q 3 weeks* *Treatment duration to PD or unacceptable toxicity **Vinorelbine dose per institutional preferenceAndersson M, et al. J Clin Oncol. 2011;29(3):264-271.
    • DOUBLETS
    • IMPORTANT LESSONS FROM HER-2 + MBC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on •Several possible combinations with cytotoxic and endocrine agents•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • Trastuzumab Beyond Trastuzumab: GBG-26 Study MBC HER2-positive Progression under trastuzumab-based first-line therapy (TFI < 6 weeks) with taxane (n = 114) or monotherapy or nontaxane (n = 42) R Capecitabine 2500 mg/m2 bid d1-14 q21 days + Capecitabine 2500 mg/m2 continuation of bid d1-14 q21 days trastuzumab 6 mg/kg q3 weeks (n = 78) (n = 78)R, randomization;TFI, treatment-free interval;MBD, metastatic breast cancerVon Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.
    • Continuation of Trastuzumab Prolongs Time to Progression by Nearly 3 Months Trastuzumab + Capecitabine (n = 78) 1.0 + Capecitabine (n = 78) + ++ HR = 0.69 (two-sided P = .0338; 0.8 + one-sided P = .0169) + + + + 0.6 PFS Probability + + 0.4 + + + ++ + ++ + 0.2 5.6* 8.2* + + + 0.0 0 10 20 30 40 Time from 1st progression, months 74 40 15 8 5 3 2 1 1 77 55 29 12 4 3 1 1 1 *Median TTP in monthsVon Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006. TTP, time to progression; HR hazard ratio
    • Lapatinib Beyond Trastuzumab: EGF 100151 Study• Progressive, HER2+ MBC R Lapatinib 1250 mg PO qd or LABC A continuously +• Previously treated with N capecitabine 2000 mg/m2/d anthracycline, taxane, and po days 1-14 q 3 weeks D trastuzumab* O• No prior capecitabine M I Z Capecitabine 2500 mg/m2/d PO days E 1-14 q 3 weeksStratification:• Disease sites Patients on treatment until• Stage of disease progression or unacceptable toxicity, then followed for survival *Trastuzumab must have been administered for metastatic disease!! LABC, locally advanced breast cancer; MBC, metastatic breast cancer Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543. Geyer C, et al. N Engl J Med. 2006;355(26):2733-2743.
    • Kaplan-Meier Estimates of Time to Progression inITT Population by Independent Review Committee HR 0.57 (95% CI, 0.43–0.77; P = .00013) Median TTP 6.2 months (lapatinib plus capecitabine) 4.3 months (capecitabine monotherapy) Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543.
    • CEREBEL Study: A Phase III Randomized Open-Label Study of Lapatinib plus Capecitabine vs Trastuzumab + Capecitabine in HER2-Positive Metastatic Breast Cancer Inclusion Criteria: • Stage IV HER2+ breast cancer • Prior anthracycline and a R Capecitabine 2500 mg/m2 bid d1-14 q21 taxane days • Prior treatment with CT, A + trastuzumab, HT, RT is Trastuzumab loading dose 8 mg/kg→ permitted N 6 mg/kg q3 weeks • LVEF ≥50%, normal organ D function O M Main Exclusion Criteria: I Lapatinib 1250 mg PO qd continuously • History and/or current + evidence of CNS metastases Z capecitabine 2000 mg/m2/d • Prior therapy with lapatinib or E PO days 1-14 q3 weeks ErbB2 inhibitor other than trastuzumab • Primary endpoint: Incidence of CNS metastases at site of first relapse • Secondary endpoints: Incidence of CNS progression at any time, time to first CNS progression, PFS, OS, ORR, CBR, duration of response, toxicity, pharmacogenetics, and biomarker analysis
    • IMPORTANT LESSONS FROM HER-2 + MBC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on •Several possible combinations with cytotoxic and endocrine agents•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • EGF104900: Phase III Study Evaluated Dual HER2 Blockade Lapatinib 1500 mg/d PO• HER2 (FISH+/IHC3+) (n = 148) metastatic breast Primary endpoint: R cancer • Progression-free• Progression on A survival – Anthracycline N D Secondary endpoints: – Taxane Crossover allowed to lapatinib + • Overall survival – Trastuzumab O trastuzumab if progression after at M • Overall response• Progression on least 4 weeks on therapy rate most recent I Z • Clinical benefit rate trastuzumab regimen E Lapatinib 1000 mg/d PO + trastuzumab 4→2 mg/kg IV weekly (n = 148) • Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks • Steady state of single-agent lapatinib occurs at approximately 7 days Blackwell KL, J Clin Oncol 2010;28(7):1124-1130. Blackwell KL, et al. Cancer Res. 2009;69(24 Suppl): Abstract 61.
    • EGF104900: Significant Overall Survival (OS) Benefit With Trastuzumab + Lapatinib Following Disease 100 Progression L L+T N = 148 N = 148 80% 80 Died, N (%) 113 (78) 105 (72) Median, months 9.5 14.0 Survival, % 60 70% 56% Hazard ratio (95% CI) .74 (.57-.97) Log-rank P-value .026 6 Month OS 40 41% 20 12 Month OS 0 0 5 10 15 20 25 30 35 Time from Randomization, monthsPatients at risk: L 148 121 88 64 43 25 1 L+T 148 102 65 47 28 13 Blackwell KL, et al. Cancer Res. 2009;69(Suppl 2): Abstract 61.
    • IMPORTANT LESSONS FROM HER-2 + MBC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on •Several possible combinations with cytotoxic and endocrine agents•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • Incidence of CNS Metastases in Trastuzumab-Treated Patients Case Series Patient Population # Overall %Bendell et al, 2003 Trastuzumab-treated 42 123 34Clayton et al, 2004 Trastuzumab-treated 23 93 25Lai et al, 2004 Trastuzumab-treated 38 79 48.1Lower et al, 2003 Trastuzumab-treated 22 87 26 Non-trastuzumab-treated 58 190 31Pinder et al, 2007 Trastuzumab-treated first-line 95 231 41 Non-trastuzumab-treated 12 61 20Shmueli et al, 2004 Trastuzumab-treated 10 41 21Stemmler et al, 2006 Trastuzumab-treated 42 136 30.9Yardley et al, 2007 HER2-positive MBC 236 768 30.7Yau et al, 2006 Trastuzumab-treated 23 87 26.4 Leyland-Jones B. J Clin Oncol . 2009;27(31):5278-5286.
    • Trastuzumab Improves Survival in Patients With mCNS Disease: U S Retrospective Analysis Survival (%) 100 HER2 positive, trastuzumab (n = 36) HER2 positive, no trastuzumab (n = 11) 80 HER2 negative (n = 48) 60 P<.0001 40 20 Time from diagnosis of 0 mCNS disease 0 10 20 30 40 (months)Kirsch DG, et al. J Clin Oncol. 2005;23(9):2114-2116.
    • LANDSCAPE STUDY: a FNCLCC phase II study with lapatinib andcapecitabine in pts with brain metastases from HER-2+ MBC before whole brain RT Primary endpoint: CNS volumetric response CNS-OR: 29/43 = 67.4% (95% CI: 52-81)CNS volumetric change N = 43 (%)≥ 80% reduction 9 (20.9)50-<80% reduction 20 (46.5)20- <50% reduction 6 (14)> 0- <20% reduction 2 (4.7)Progression* 6 (14)* 2 patients had extra-CNS disease progression NSS improvement: 14/24 = 58.3% (95% CI: 36.6-77.9) Bachelot et al, ASCO 2011
    • IMPORTANT LESSONS FROM HER-2 + BC • Crucial role of patient selection • ABC: primary or metastatic HER-2 status? •Importance of starting anti-HER-2 agent early on•Continue HER-2 blockade beyond progression (change of paradigm in ABC) • The principle of dual blockade • Problem of brain metastases • Even with target/targeted drug resistance occurs
    • COULD BLOCKAGE OF GRF PATHWAY(S) DELAY and/or PREVENT THE ONSET OF HORMONE RESISTANCE? HORMONE-SENSITIVE HORMONE-RESISTANT BREAST CANCER BREAST CANCER• SWITCH TOWARDS GRF SIGNALLING PATHWAYS• GAIN OF SENSITIVITY TO ANTI-GROWTH FACTOR PATHWAY DRUGS Adapted from R Nicholson, Tenovus Institute, Cardiff, UK
    • EGF30008: Phase III, Randomized, Double-Blind Controlled Trial: Study Design Patient Population: • ER+ and/or PgR+ • Postmenopausal R • HER2+, HER–/Unknown Letrozole 2.5 mg daily + • Stage IIIb/IIIc/IV A placebo • No prior treatment for N metastatic breast cancer D (MBC) O M Stratification: Letrozole 2.5 mg daily + • Disease sites I lapatinib 1500 mg daily • Bone only/visceral or Z soft tissue E • Interval since adjuvant tamoxifen therapy N = 1286 (including n = 219 HER2+) • <6 mo / ≥6 mo or noneJohnston S, et al. J Clin Oncol. 2009;27(33):5538-5546.
    • Progression-Free Survival: HER2-Positive PopulationS Johnston, SABCS 2008, Abst # 46 FOR HER2-positive patients 5 months benefit in PFS No difference in OS Overall Survival: HER2-Positive Population S Johnston, SABCS 2008, Abst # 46Johnston S, et al. Cancer Res. 2009;69(Suppl 2): Abstr 46
    • Progression-Free Survival: ITT and HER2-Negative Populations HER2-Negative* For HER2-negative patients NO BENEFIT BUTJohnston S, et al. Cancer Res. 2009;69(Suppl 2): Abstract 46.
    • PFS: HER2-Negative Patients (N = 952) ≥6 Months Since D/C <6 Months Since D/C of Tam (33%) or No Tam (67%) of Tam • Median Tam duration 5 years • Median Tam duration 2.8 years • Median time since D/C 3.5 years • Median time since D/C 1 month Benefit in Tam- resistantJohnston S, et al. Cancer Res. 2009;69(Suppl 2): Abstract 46.
    • Numerous Treatments for HER2-Positive Breast Cancer in DevelopmentHER2 dimerization Pertuzumab inhibitor Monoclonal antibody that inhibits dimerization of HER2 T-DM1 HER2 ADC Trastuzumab-based ADC-delivering cytotoxic drug (DM1) specifically to HER2 + tumor cells PI3K inhibitors eg, GDC0941, BKM120 Small molecule selectively binding PI3K isoforms to inhibit the PI3K / Akt signaling pathway Afatinib Tyrosine Reversible inhibitor of EGFR and HER2 tyrosine kinase kinase inhibitors Neratinib Irreversible inhibitor of EGFR, HER2 and HER4 tyrosine kinase mTOR eg, Everolimus inhibitors Small molecule inhibiting mTOR signal transductionHSP 90 inhibitors eg, Tanespimycin Antineoplastic antibiotic inhibiting HSP 90 VEGF receptor eg, Bevacizumab inhibitors Monoclonal antibody inhibiting VEGFADC: antibody-drug conjugate.T-DM1: trastuzumab DM1. PI3K: phosphoinositide 3-kinase.EGFR: epidermal growth factor receptor. mTOR: mammalian target of rapamycin. HSP: heat-shock protein.VEGF: vascular endothelial growth factor.
    • Prognosis in MBC by HER2 Status and by Therapy with Trastuzumab n = 2,091 Patients 1 y survival HR (median f/u = 16.9 mo) (%) (95% CI) 118 70.2% HER2-pos -- (5.6%) (60.3%, 78.1%) 1,782 75.1% HER2-neg 0.56 (85.3%) (72.9%, 77.2%) (0.45-0.69, HER2-pos treated 191 86.6% p = 0.0001) with trastuzumab (9.1%) (80.8%, 90.8%) Dawood et al, ASCO abstract 1018, 2008Courtesy A Wolf
    • BACK-UP
    • Significant Rate of Discordancy Between Primary and Metastases Amir Curigliano 2010 Studies Karlsson Lindstrom (n~270) (n~250) Comparing Primary (n~470) (n~118-459) Prospective Retrospective to Metastasis Retrospective3 Retrospective4 Reanalyzed1 Liver Only2 ER+  ER- 12% 11% 36% 26% ER-  ER+ 14% 25% 22% 7% HER2-  HER2+ 5% 6% nd 7% HER2+  HER2- 12% 32% nd 3%1. Amir E, et al. J Clin Oncol. 2010;28(15S): Abstract 1007. 2. Curigliano G, et al. Ann Oncol. 2011 Feb 22 [Epub aheadof print]. 3. Karlsson E, et al. J Clin Oncol. 2010;28(15S): Abstract 1009. 4. Lindstrom LS, et al. Cancer Res. 2010;70(24Suppl): Abstract S3-5.
    • MANAGEMENT OF HER-2 + BC• WHAT HAVE WE LEARNED • HER-2 + BC is a separated well identified disease • Quality of HER-2 testing is essential: Selection of pts is crucial • Trastuzumab and Lapatinib are efficacious in MBC • Overall good safety profile of anti-HER2 therapies but cardiac surveillance & management guidelines (cardiac, GI, liver, skin) needed • Trastuzumab can be combined in many different cytotoxic agents • Brain mets are an important clinical problem • Resistance does occur (mechanisms, ways to overcome it) • Many new drugs in the (near) future (how to choose between them)