The current treatment landscape for early breast cancer: Advances in cytotoxic and endocrine treatment

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1 The current treatment landscape for early breast cancer: Advances in cytotoxic and endocrine treatment Ahmad Awada, MD, PhD Head of Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Brussels, Belgium HQ/ONC/14/0007 October 2015

2 Systemic treatment of early breast cancer - plan of the talk - 1. Why chemotherapy is still an important therapeutic component 2. Which patients? Which tumors? Chemotherapy and endocrine therapy settings? 3. Role of dose-dense regimens 4. Latest advances in the neoadjuvant setting (TNBC; HER2+) 5. Perspectives (Tumor sequencing, TILs)

3 CLINICAL CASE A 61-year-old postmenopausal woman seeks your opinion 2 weeks after surgery for a 3cm invasive ductal cancer of the left breast. Two positive axillary lymph nodes. ER 7/8 PR 3/8 grade 2 Ki67 is 20% and HER2 is negative (Luminal B disease) LVEF is 60%

4 CLINICAL CASE Your recommendation as adjuvant endocrine therapy is: 1. An aromatase inhibitor upfront (5 y) 2. Tamoxifen alone (5 y) 3. Tamoxifen alone (10 y) 4. Sequential therapy: tamoxifen AI (5 y) 5. Five years of tamoxifen followed by an extended AI 6. Other

5 CLINICAL CASE In addition to endocrine therapy, should we prescribe zoledronic acid as an adjuvant antitumoral approach (pts with estrogen deprivation)?

6 CLINICAL CASE Your adjuvant chemotherapy recommendation is 1. CMF x 6 cycles or AC x4 2. TC x 4 3. Anthracycline-based chemotherapy x6 (eg, FEC x 6) 4. Anthracycline plus taxane-based chemotherapy (eg, FEC taxane or TAC x 6) 5. Dose-dense ECx4 taxane (docetaxel x 4 or paclitaxel wx12) 6. Anthracycline + taxane/carboplatin based 7. Chemotherapy + bevacizumab 8. Other Of note: each chemotherapy option is followed by endocrine therapy.

7 1. Why chemotherapy is still an important therapeutic component in early BC The Basis of Systemic Therapy = Chemotherapy except for luminal A diseases! Luminal B tumors (ER+/HER2-) Anders CK. San Antonio Breast Cancer Symposium 2013: Abstract ES03-2.

8 2. Adjuvant therapy of breast cancer: which patients? Which tumors? Which biology? Patients Characteristics Age Comorbidities (organs dysfunction) T size N status Metastases? Circulating tumor DNA or cells ER PR HER2 Ki67 PIK3CA mutations? Gene profiling? TILs? HRD? TREATMENT BURDEN TUMOR BURDEN TUMOR BIOLOGY Host tolerance to chemotherapy Here resides the decision to escalate / de-escalate the chemotherapy Here are the targets! Targeted therapies (endocrine and HER2 therapies)

9 Prognostic and/or predictive marker: PiK3CA mutations PIK3CA mutations 30% of BC (mainly HR+) Good outcome (HR+) Sensitivity to everolimus (HER2+/BOLERO 1 & 3) Lower pcr in the neoadjuvant Solid rationale to include PiK3CA mutation as a biological marker Challenge: which technic? (ASCO 2015,Abs 516, 511, 512)

10 Predictive markers: Homologous recombination deficiency scoring (HRD) Homologous recombination deficiency scoring (HRD) More and more studied in TNBC/basal-like (and high risk HR+) The magnitude of sensitivity prediction to platinum or PARPi is unclear The application of HRD scoring needs validation (ASCO 2015, Abs 521, 1018, 1004)

11 TAILORx and MINDACT Bringing molecular prognostic signatures to daily clinical practice in a selected group of pts?! TAILORx trial: Clinical Trials.gov #NCT MINDACT study: Clinical Trials.gov # NCT %-60% 10% 30%-40% High-risk 21-gene R.S. OR High-risk 70-gene signature + High-risk adjuvant online Medium-risk 21-gene R.S. OR Discordant risk group Low-risk 21-gene R.S. OR Low-risk 70-gene signature + Low-risk adjuvant on line CHEMOTHERAPY RANDOMIZE CHEMO YES or NO (TailorX) RANDOMIZE FOR the decisionmaking tool (Mindact) ENDOCRINE THERAPY

12 Tumor-Infiltrating Lymphocytes In Breast Cancer (TILs)

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16 Lymphocyte predominant breast cancer (LP) ( 60% Str-TIL): 10% of pts Non-Lymphocyte predominant breast cancer (Non-LP) (< 60% Str-TIL): 90% of pts Arm A: Chemotherapy Arm C: Chemotherapy + Trastuzumab

17 Lymphocyte predominant breast cancer and treatment outcome: Provocative results Increasing Str- TILS ( 60%) associated with increased RFS in pts treated with chemotherapy alone Patients with non-lpbc had better RFS when treated with chemotherapy plus trastuzumab RFS: Recurrent-Free Survival

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19 Overview of the most important adjuvant chemotherapy studies in early breast cancer Doc-C Addition of capecitabine, gemcitabine, bevacizumab not beneficial AC < AC->Pac(qw) or Doc(3w) = < AC->Pac(3w) < < = = CMF < CAF/FAC < DocAC = dda/ec- >Pac(2w) < 6 cycles 4 cycles 8 cycles CEF/FEC < FEC->Doc Wildiers H,, Awada A, Belg J Med Oncol. 2014

20 3. Pure adjuvant dose-dense chemotherapy (+G-CSF) studies in early breast cancer Author (n) Citron (n = 1992) Venturini (n = 1214) Cameron (n = 4391) Cognetti (n = 2091) N status Control arm Dose dense (+CSF) Outcome 100% N+ 4xAC->4xPac(3w) 4xAC->4xPac(2w) 66% N0 6xFE60C(3w) 6xFE60C(2w) 47%N0 100% N+ 4xE100(3w)- >4xCMF/X 4x(F)E90C- >4xPac(3w) 4xE100(2w)->4xCMF/X 4x(F)E90C->4xPac(2w) DFS OS DFS = OS = DFS = OS = DFS OS 5-FU no benefit Wildiers H,, Awada A, Belg J Med Oncol. 2014

21 EBCTCG meta-analyses (2011) of studies using polychemotherapy: Five main findings (1) 1. Polychemotherapy regimens with significantly lower dose per cycle appeared less effective (role of G-CSF) 2. Standard ACx4 = standard CMFx6 3. Regimens with substantially more chemotherapy than 4AC (eg, CAF, CEF, A+T) were somewhat more effective Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2012;379(9814):

22 EBCTCG meta-analyses (2011) of studies using polychemotherapy: Five main findings (2) 4. In all chemotherapy comparisons (A+T, highercumulative-dosage anthracycline-based), 10- year overall mortality was reduced by one-third 5. In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumor diameter or differentiation, ER status, or tamoxifen use Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2012;379(9814):

23 SELECTION OF ADJUVANT ENDOCRINE THERAPY FOR POSTMENOPAUSAL PATIENTS ACCORDING TO ENDOCRINE RESPONSIVENESS AND TUMOR RISK Hormone receptors expression T U M O R R I S K High Low C H E M O T H E R A P Y Absent Intermediate High AI switch AI Upfront TAM TAM alone Switch AI TAM AI upfront ADD CHEMOTHERAPY FOR HIGH-RISK PATIENTS Premenopausal patients: Tamoxifen ± GnRH analogs or AI + GnRH analogs according to the tumor risk and side effects. *Luminal A disease

24 SELECTION OF ADJUVANT CHEMOTHERAPY REGIMENS : ACCORDING TO ENDOCRINE- RESPONSIVENESS AND TUMOR RISK Hormone receptors expression Absent Intermediate High Low A+T TC A+T Endocrine therapy Tumor risk Intermediate High Anthracyclines (A) + taxane (T) A+T: sequencially or in combination (including dose-dense) A(C) CMF (contraindication to taxane) TC: of great interest in pts at risk of cardiac failure ADD Endocrine therapy

25 Chemotherapy regimens used in pivotal studies for HER2+ breast cancer: significant positive outcome mainly when trastuzumab combined with taxane Trastuzumab (T) use Concurrent Sequential Concurrent versus sequential Study Control arm Trastuzumab arm BCIRG 006 NSABP B-31 HERA 4xAC->4xDoc 4xAC->4xPac(3w) or 12xPac(qw) Chemotherapy 4xAC->4xDoc+T 6xDocCarboT (TCH)* 4xAC->4xPac(3w) or 12xPac(qw) +T Chemo->T1y Chemo->T2y PACS-04 6xFEC or 6xEDoc 6xFEC or 6xEDoc->T1y NCCTG N9831 4xAC->12xPac(qw) 4xAC->12xPac(qw)+T1y 4xAC->12xPac(qw)->T1y *of great interest in pts at risk of cardiac failure ALTTO trial (+ lapatinib): negative study T = trastuzumab; y = years; Carbo = carboplatin Wildiers H, Awada A, Belg J Med Oncol. 2014

26 Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3 randomized, placebo-controlled trial (ExteNET))

27 Study Design

28 Primary Endpoint: Invasive DFS (ITT) 2,3 %

29 ExteNET: Summary Absolute difference in invasive disease-free survival at 2 years is 2.3 % in favor of neratinib Extenet Summary

30 4. Neoadjuvant setting: An attractive approach for clinical practice and for translational research Biopsy Standard preoperative therapy Surgery Ki67 Gene profiling Tumor sequencing PET/CT Standard preoperative therapy + new agent Molecular Markers; PET/CT Real-time evaluation of primary tumor response Postoperative therapy adapted based on the induction efficacy (investigational) Caveat: Difference in biology of micrometastasis versus primary tumor?!

31 Selection of important neoadjuvant randomized trials incorporating taxanes Author (n) Control arm Experimental arm Outcome NSABP-B27 (n = 2411) Aberdeen (n = 162) ACCOG (n = 363) Dieras (n = 200) Metaanalysis (n = 2455); 7 trials 4xAC->S PR/CR after 4xCVAP: 4xCVAP 6xAC 4xAC-> Anthracycline based 4xAC->S->4xDoc 4xAC->4xDoc->S PR/CR after 4xCVAP: 4xDoc 4xADoc 4xAPac Anthracycline based + taxane pcr with Doc DFS = OS = pcr DFS OS pcr = DFS = OS = pcr DFS OS pcr with sequential, but not concomitant taxane DFS = S = surgery; pcr = pathological complete response rate (in breast and axilla); PR = partial response; CR = complete response Wildiers H, Awada A, Belg J Med Oncol. 2014

32 Cortazar, et al. Cancer Res. 2012;72(24)suppl 3:Abstract S1-11.

33 Weekly non-pegylated liposomal doxorubicin + paclitaxel ± carboplatin as primary therapy for TNBC or HER+ tumors (1) von Minckwitz G, et al. ASCO 2013:abstract 1004; von Minckwitz G, et al. Lancet Oncol. 2014;15(7):

34 Weekly non-pegylated liposomal doxorubicin + paclitaxel ± carboplatin as primary therapy for TNBC or HER+ tumors (2) BRCAness TNBC benefit most from carboplatin von Minckwitz G, et al. ASCO 2013:abstract 1004; von Minckwitz G, et al. Lancet Oncol. 2014;15(7):

35 All TNBC Sikov W, et al. San Antonio Breast Cancer Symposium 2013: Abstract S5-01.

36 CALGB Study: PCR Result All TNBC Sikov W, et al. San Antonio Breast Cancer Symposium 2013: Abstract S5-01.

37 41 % 54 %

38 Should carboplatin now be standard in the neoadjuvant setting? Probably not except for a subgroup of patients (which one?), BRCA mutated tumors, TILS, HRD ) Cortazar, et al. Cancer Res. 2012;72(24)suppl 3:Abstract S1-11.

39 Dual HER2 targeting together with a taxane

40 Dual HER2 + taxane in the neoadjuvant setting: doubling pcr mainly in HR negative tumors NEO-SPHERE Gianni L, et al. Lancet Oncol Jan;13(1): Single HER2 inhibition + chemotherapy Trastuzumab Docetaxel Pertuzumab Docetaxel Dual HER2 inhibition + chemo Trastuzumab Pertuzumab Docetaxel Dual HER2 inhibition No chemotherapy! Trastuzumab Pertuzumab ITT 29% 24% 46% 17% NEO-ALTTO Baselga J, et al. Lancet. 2012;379(9816): Single HER2 inhibition + chemotherapy Dual HER2 inhibition Trastuzumab Paclitaxel Lapatinib Paclitaxel Trastuzumab Lapatinib Paclitaxel ITT 29% 25% 51% HR negative tumors benefit most from dual HER inhibition

41 DUAL HER-2 THERAPY IN THE NEOADJUVANT SETTING: CONCLUSIONS (2015) Trastuzumab + lapatinib + paclitaxel: Standard use not justified in view of the negative results of ALTTO trial Trastuzumab + pertuzumab + docetaxel: Of interest in locally «bulky» disease, HR negative Standard use await APHINITY trial Dual HER-2 therapy alone Intensify translational research to help in the selection of patients candidates for dual HER-2 therapy without chemotherapy Of interest in elderly patients?

42 Neoadjuvant therapy T-DM1 (12 weeks) ± endocrine therapy (ET) versus ET + trastuzumab in HER2+/HR+ tumors pcr T-DM1 : 40.5% T-DM1 + Endocrine treatment: 46% Trastuzumab + ET : 7% Ki-67 (3w vs baseline) not predictive of pcr Validation in a phase 3 trial is needed as well as the correlation with DFS and OS (ASCO 2015, Abs 506)

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44 CLINICAL CASE A 61-year-old postmenopausal woman seeks your opinion 2 weeks after surgery for a 3cm invasive ductal cancer of the left breast. Two positive axillary lymph nodes. ER 7/8 PR 3/8 grade 2 Ki67 is 20% and HER2 is negative (Luminal B disease) LVEF is 60%

45 CLINICAL CASE Your recommendation as adjuvant endocrine therapy is: 1. An aromatase inhibitor upfront (5 y) 2. Tamoxifen alone (5 y) 3. Tamoxifen alone (10 y) 4. Sequential therapy: tamoxifen AI (5 y) 5. Five years of tamoxifen followed by an extended AI 6. Other

46 CLINICAL CASE In addition to endocrine therapy, should we prescribe zoledronic acid as an adjuvant antitumoral approach (pts with estrogen deprivation)?

47 CLINICAL CASE Your adjuvant chemotherapy recommendation is 1. CMF x 6 cycles or AC x4 2. TC x 4 3. Anthracycline-based chemotherapy x6 (eg, FEC x 6) 4. Anthracycline plus taxane-based chemotherapy (eg, FEC taxane or TAC x 6) 5. Dose-dense ECx4 taxane (docetaxel x 4 or paclitaxel wx12) 6. Anthracycline + taxane/carboplatin based 7. Chemotherapy + bevacizumab 8. Other Of note: each chemotherapy option is followed by endocrine therapy.

48 THANK YOU