The NeOAdjuvant Herceptin Study (NOAH) was an international phase III trial evaluating the efficacy and safety of chemotherapy with an anthracycline and taxane, followed by cyclophosphamide, methotrexate and 5-fluorouracil (CMF), with or without trastuzumab, in women with newly diagnosed locally advanced breast cancer ( LABC) 1 . The design of the study provided the opportunity to compare the results of the same chemotherapy regimen without trastuzumab in a parallel cohort of women with ErbB2-negative breast cancer. In this multicentre, randomised, open-label trial, women with ErbB2+ (IHC 3+ or FISH+) LABC were randomised to receive 3 cycles of doxorubicin (60 mg/m) and paclitaxel (150 mg/m) every 3 weeks, 4 cycles of paclitaxel (175 mg/m every 3 weeks) and 3 cycles of CMF (cyclophosphamide 600 mg/m, methotrexate 40 mg/m, 5-fluorouracil 600 mg/m every 4 weeks) on days 1 and 8, with or without concomitant trastuzumab (8 mg/kg loading dose then 6 mg/kg every 3 weeks for 1 year) before surgery. In parallel, LABC patients screened as ErbB2-negative (IHC 0/1+) received the same chemotherapy regimen. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary endpoints were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety. Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. SABCS 2008 (Dec); Abstract 31 5 Neoadjuvant treatment
327 patients were enrolled in NOAH. Inflammatory breast cancer was present in 27% of ErbB2+ vs. 14% of ErbB2-negative tumours, while 35% vs. 64%, respectively, were hormone-receptor positive. In this prospective intent-to-treat analysis, the pCR rate for ErbB2+ patients was 43% when trastuzumab was added to chemotherapy, and 23% in the control arm (p=0.002); of note, the same chemotherapy regimen yielded a 17% pCR in ErbB2-negative patients (p=ns). Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. SABCS 2008; Abstract 31 and presentation pCR and tpCR
Event-free survival (EFS) was analysed after 88 events in the ErbB2+ group (n=228). EFS rate at 3 years was significantly better in the trastuzumab arm (70.1%) compared with chemotherapy alone (53.3%, hazard ratio [HR] 0.56; p=0.007). EFS rate in the ErbB2-negative arm was 67.4%. The addition of trastuzumab to chemotherapy in the neoadjuvant setting was well tolerated, with acceptable cardiac safety. The authors concluded that neoadjuvant trastuzumab significantly increased EFS in patients with ErbB2+ LABC, establishing neoadjuvant trastuzumab with chemotherapy as a standard treatment option in women with ErbB2+ LABC. Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. SABCS 2008; Abstract 31 and presentation 5 Neoadjuvant treatment
Herceptin combination Docetaxel Breast cancer: metastatic-first line Breast cancer: metastatic Trial Pivotal trial Response Efficacy
Transcript of "MON 2011 - Slide 4 - E. Senkus-Konefka - Treatment of metastatic disease and neoadjuvant therapy"
Elżbieta Senkus-Konefka Dept. of Oncology and Radi otherapy , Medical University of Gdańsk, Poland ESO Masterclass 2011 15th century painting in Santa Maria della Grazia in Milan Breast cancer - neoadjuvant therapy and t reatment of metastatic disease
<ul><li>POSSIBLE </li></ul><ul><li>Earlier treatment of distant micrometastases </li></ul><ul><li>In vivo sensitivity test of systemic agents </li></ul><ul><li>Improvement of survival vs. local therapy alone </li></ul><ul><li>PROVEN </li></ul><ul><li>Improved operability rates of initially inoperable tumors </li></ul><ul><li>Improved rates of breast-conserving surgery </li></ul><ul><li>Translational correlative studies </li></ul>POSSIBLE DISADVANTAGES T umour progression i f no response to systemic therapy Loss of pathological prognostic information ADVANTAGES
Candidates for neoadjuvant therapy <ul><li>LOCALLY ADVANCED or INFLAMMATORY BC </li></ul><ul><li>„ LARGE” OPERABLE BC </li></ul>Primary systemic therapy = treatment of choice Primary systemic therapy = option
Which patients benefit most? Huober, BCRT 2010
How important is pCR in relation to other prognostic factors? Liedtke, JCO 2008
Can treatment results be improved? von Minckwitz, BCRT 2010 ?correlation with long term outcomes
Is chemotherapy indispensable? Semiglazov, Cancer 2007
Is chemotherapy indispensable? Semiglazov, Cancer 2007
HTH for ER + Targeted therapy MD Anderson study Buzdar , JCO 2005 Trastuzumab weekly x 24 Paclitaxel q3w x 4 FEC x 4 Paclitaxel q3w x 4 FEC x 4 n=23 n=19 Stage II Her2 + IHC 3+ / FISH +
Targeted therapy <ul><li>MD Anderson study </li></ul>pCR DFS Buzdar , JCO 2005, Clin Cancer Res 2007
NOAH: trastuzumab in the neoadjuvant setting in ErbB2+ LABC Gianni , Lancet 2010 AP P CMF AP P CMF T + P T + CMF T continued R n= 1 15 n=99 n= 1 13 Surgery + RT Surgery + RT Surgery + RT T + AP ErbB2 ( + ) ErbB2 ( - )
NOAH: pathological complete response Gianni , Lancet 2010 0 10 20 30 40 50 With H Without H HER2 negative With H Without H HER2 negative Patients, % HER2 positive HER2 positive BREAST ONLY BREAST AND NODES 43% 22% 17% 38% 19% 16% p=0.37 p=0.002 p=0.003 p=0.43
NOAH study results (HER2+) Gianni , Lancet 2010 0 6 12 18 24 30 36 Patients Events HR 95% CI p T + C T 1 17 18 0.62 0.34–1.23 0.11 C T 1 18 26 0.25 0.50 0.75 1.00 0.00 Months Patients Events HR 95% CI p T + C T 1 17 36 0.59 0.36–0.85 0.013 C T 1 18 51 0 6 12 18 24 30 36 42 0.25 0.50 0.75 1.00 Overall survival 0.00 Months 42 Event-free survival Probability, EFS Probability, overall survival
New targeted agents ↑ pCR -> ??? long term outcome
Meaning of pCR <ul><li>surrogate for cure? </li></ul><ul><li>selection of best prognosis patients? </li></ul>will higher pCR rate translate into improved long term outcome?
Does pCR translate into long term outcome??? Gianni , Lancet 2010 EFS: HER2 + (without trastuzumab) vs HER2 - NOAH pCR rates 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 42 Probability, EFS Months CT, HER2 + CT, HER2 - 0 10 20 30 40 50 With H Without H HER2 - With H Without H HER2 - Patients, % HER2 + HER2 + BREAST ONLY BREAST AND NODES 43% 22% 17% 38% 19% 16% p=0.37 p=0.002 p=0.003 p=0.43
<ul><li>NSABP B-27 </li></ul>Does pCR translate into long term outcome??? Rastogi, JCO 20 08 pCR rate DFS overall survival
… for metastatic breast cancer there are few approved standards of care…
(1) The management of metastatic breast cancer (MBC) is complex; therefore, involvement of all appropriate specialties in a multi/interdisciplinary team (medical, radiation, surgical and imaging oncologists, palliative care, psycho-social, among others) is crucial.
Systemic management of breast cancer supportive care chemo- therapy hormono- therapy targeted therapy
(2) From the first diagnosis of MBC, patients should be offered personalised appropriate psychosocial, supportive, and symptom-related interventions as a routine part of their care.
(3) Following thorough assessment and confirmation of MBC, the realistic treatment goals must be specified and discussed. Patients and family members should be invited to participate in all decision-making.
Primary goals in the treatment of MBC <ul><li>Maintenance of quality of life and function </li></ul><ul><li>Reduction of cancer related symptoms and complications </li></ul><ul><li>Prolongation of survival </li></ul>
Management of Advanced Breast Cancer: Efficacy vs Toxicity
(4) A small but very important subset of MBC patients, for example, those with a solitary metastatic lesion, can achieve complete remission and a long survival. For these selected patients, a more aggressive and multidisciplinary approach should be considered .
Is MBC curable? <ul><li>RATIONALE: in the era of improved systemic control with new therapies a removal of intact primary or oligometastatic foci may prevent further tumor spread and allow for long-term disease control </li></ul>
Surgery for primary in MBC? 0.67 ND 5179/9197 (56.3%) Khan 2003 0.53 surgery: 26.8 no surgery: 12.6 187/409 (45.7%) Fields 2007 0.5 not reached predicted: 54 82/224 (37%) Babiera 2006 Rao 2008 0.71 surgery: 27.1 no surgery: 16.8 242/395 (61.3%) Blanchard 2008 0.63 surgery: 27 no surgery: 12 4578/9734 (47%) Gnerlich 2007 margin (-): 0.6 margin (+): NS margin (-): 26 margin (+): 17 no surgery: 13 127/300 (42%) Rapiti 2006 margin (-): 0.61 margin (+): 0.75 total mastectomy: 31.9 partial mastectomy: 26.9 no surgery: 19.3 9162/16023 (57.2%) Khan 2002 HR for OS (surgery vs not) median OS (months) N° patients: operated/all (%) Author
Surgery for primary in MBC? 0.67 ND 5179/9197 (56.3%) Khan 2003 0.53 surgery: 26.8 no surgery: 12.6 187/409 (45.7%) Fields 2007 0.5 not reached predicted: 54 82/224 (37%) Babiera 2006 Rao 2008 0.71 surgery: 27.1 no surgery: 16.8 242/395 (61.3%) Blanchard 2008 0.63 surgery: 27* no surgery: 12* 4578/9734 (47%) Gnerlich 2007 margin (-): 0.6 margin (+): NS margin (-): 26* margin (+): 17* no surgery: 13* 127/300 (42%) Rapiti 2006 margin (-): 0.61 margin (+): 0.75 total mastectomy: 31.9 partial mastectomy: 26.9 no surgery: 19.3 9162/16023 (57.2%) Khan 2002 HR for OS (surgery vs not) median OS (months) N° patients: operated/all (%) Author
Surgery for primary in MBC? Rapiti, JCO 2006 only selection bias?
Resection of metastases? <ul><li>467 cases of the international registry of lung metastases </li></ul>Friedel , Eur J Cardio-Thor Surg 2002
(5) Minimal staging work-up for MBC includes a history and physical examination, complete haematology and biochemistry, and imaging of the chest, abdomen and bone.
(5) – contd. The clinical value of tumour markers is not well established for diagnosis or follow-up; however, their use as an aid to evaluate response to treatment, particularly in patients with nonmeasurable disease, is acceptable.
Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009
Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009, Wilking 2011 biology or suboptimal treatment???
(6) <ul><li>Treatment choice should take into account: </li></ul><ul><li>endocrine responsiveness, </li></ul><ul><li>HER-2 status, </li></ul><ul><li>menopausal status, </li></ul><ul><li>disease-free interval, </li></ul><ul><li>previous therapies and response obtained, </li></ul><ul><li>tumour burden (defined as number and site of metastases), </li></ul><ul><li>biological age and co-morbidities (including organ dysfunctions), </li></ul><ul><li>performance status, </li></ul><ul><li>need for rapid disease/symptom control, </li></ul><ul><li>socio-economic and psychological factors, </li></ul><ul><li>patient’s preference </li></ul><ul><li>and available therapies in the patient’s country (this list is not exhaustive). </li></ul>
systemic treatment of breast cancer previous treatments anthracycline dose taxane use late sequelae tumor organ involvement biology tumor bulk patient age performance status co-morbidities clinical trial ? treatment toxicity efficacy preference impact on QoL Optimal treatment choice DFI cardiac damage
(7) Endocrine therapy is the preferred option for hormonal receptor-positive disease, unless there is concern or proof of endocrine resistance. Endocrine therapy of breast cancer is a very old targeted treatment…
<ul><li>For pre-menopausal women, tamoxifen combined with ovarian suppression/ablation is the first choice except for tamoxifen-resistant tumors. </li></ul>
The optimal first-line hormonal treatment for postmenopausal patients is an aromatase inhibitor ; however, tamoxifen remains a viable option. Optimal post-aromatase inhibitor treatment is uncertain, but tamoxifen , fulvestrant or a different aromatase inhibitor are possible options .
<ul><li>Maintenance of hormonal treatment after chemotherapy is not established, but is reasonable. </li></ul><ul><li>Concomitant chemo + endocrine therapy should be discouraged. </li></ul>
(8) Trastuzumab should be offered early to all HER-2-positive MBC patients, either combined with chemo or endocrine therapy or as a single agent .
Lapatinib + letrozole Johnston , JCO 2009 HER2(–) patients with <6 months since discontinuation of adjuvant tamoxifen
Patients progressing on an anti-HER-2 therapy combined with a cytotoxic agent should be offered a second combination of agents since it is important to keep blocking the HER-2 pathway in these tumours. Lapatinib combined with a cytotoxic agent is a viable option for patients progressing on trastuzumab .
GBG-26 Von Minckwitz, JCO 2009 Continuing trastuzumab beyond progression… capecitabine + trastuzumab (n=78) MBC HER2 + progressing on trastuzumab capecitabine (n=78) R
Continuing trastuzumab beyond progression… 54.0% 75.3% 27.0% 48.0% CR + PR p = 0.011 clinical benefit p = 0.0068 Von Minckwitz, JCO 2009
(9) Both combination and sequential single agent monotherapy are reasonable first-line chemotherapy options. I n the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control sequential monotherapy i s the preferred choice in MBC.
(9) – contd. Patient- and disease-related factors should be used to choose between combination and sequential single-agent chemotherapy for MBC. Duration of each regimen and number of regimens should be tailored to each individual patient. Efficacy Toxicity
Median PFS/TTP (mths) Combination vs single agent? Pacilio 2006 9 months 0 2 4 6 8 10 Mu-oz 2006 Zielinski 2005 Albain 2004 O’Shaughnessy 2002 Jassem 2001 Mu-oz 2006 Seidman 2004 Chan 1999 Chan 1999 ET Gem + Vin Flu + Epi GT TX AT Vinorelbine Paclitaxel Doxorubicin Docetaxel
Combination vs single agent? m edian OS (mths) O’Shaughnessy 2002 Melemed 2007 Sledge 2003 Seidman 2004 Jones 2005 24 months 0 5 10 15 25 30 20 paclitaxel q3w paclitaxel q1w TX GT docetaxel
Combination vs single agent? <ul><li>E1193 </li></ul>Sledge, JCO 2003 doxorubicin vs paclitaxel vs doxo + paclitaxel time to treatment failure p=0.011 overall survival p=0.77
Combination vs single agent? randomized studies with planned cross-over Cardoso, JNCI 2009
Optimal therapy choice? <ul><li>monotherapy </li></ul><ul><ul><li>slow natural history </li></ul></ul><ul><ul><li>older age </li></ul></ul><ul><ul><li>poor PS </li></ul></ul><ul><ul><li>patient’s choice (continuing to work, etc.) </li></ul></ul><ul><li>combination chemotherapy </li></ul><ul><ul><li>rapid progression </li></ul></ul><ul><ul><li>need for rapid symptom control </li></ul></ul><ul><ul><li>visceral involvement </li></ul></ul><ul><ul><li>good PS </li></ul></ul>
<ul><li>in the past </li></ul>Chemotherapy – paradigm change now progression progression progression
(10) There are few proven standards of care in MBC management. Therefore, inclusion of patients in well-designed, independent, prospective randomised trials must be a priority whenever available. Every proposed option must have a sound scientific rationale, preferably evidence-based.
(11) The medical community is aware of the problems raised by the cost of MBC treatment. Balanced decisions should be made in all instances, but the patient’s well-being, length and quality of life must always be the main decision factors.
Bewacizumab Miller, NEJM 200 7 E2100 – overall survival no effect on survival!!! Months 1.0 0.8 0.6 0.4 0.2 0 HR=0.869 Log-rank test: p=0.1374 Paclitaxel + Avastin: median OS 26.5 months Paclitaxel: median OS 24.8 months OS estimate 0 6 12 18 24 30 36 42 48 54 60
Bewacizumab AVADO – progression free survival Mile s , ASCO 2008 BEV 7.5 mg/kg BEV 15 mg/kg Median 8.0 vs 8.7 mths HR 0 .79 (.63–.98) P = .0318 Mos PFS estimate 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 HR 0 .72 (.57–.90) P = .0036 Mos PFS estimate 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 Bev + Docetaxel (n = 248) Placebo + Docetaxel (n = 241) Median 8.0 vs 8.8 mths
(12) Formal (not just informal) quality of life assessments provide useful information and should be encouraged. If collected, such information should be integrated with that from clinic assessments to allow management decisions on initiating, changing, or stopping drug therapy.
Difficult issues triple-negative breast cancer
Inhomogenous disease „ triple negative” BC basal-like BC BRCA1 -related BC no single treatment is going to be effective high-grade ductal Ca metaplastic Ca apocrine Ca secretory Ca adenoid cystic Ca myoepithelial Ca medullary Ca high-grade lobular Ca neuroendocrine Ca
Choice of ChT <ul><li>anthracyclines? </li></ul><ul><ul><li>theory – ideal compounds </li></ul></ul><ul><ul><ul><li>frequent overexpression of Topo II </li></ul></ul></ul><ul><ul><ul><li>BRCA mutation/dysfunction -> aberrant DNA repair </li></ul></ul></ul>
Anthracyclines? <ul><li>clinical data conflicting </li></ul>Di Leo, SABCS 2008, Cheang , ASCO 2009 NCIC-CTG MA5 A better CMF better HER2 amplified Triple negative Highly horm-sensitive Moderately horm-sensitive Metaanalysis British Columbia population-based
Choice of ChT <ul><li>taxanes? </li></ul><ul><ul><li>theory </li></ul></ul><ul><ul><ul><li>80% of TNBC are p53 mutant – potential benefit of taxanes? </li></ul></ul></ul>
Taxanes? <ul><li>clinical data conflicting </li></ul>Hayes, NEJM 2007, Ellis, Lancet 2009 CALGB 9344 all patients N+ patients TACT DFS
Choice of ChT <ul><li>platinum? </li></ul><ul><ul><li>theory </li></ul></ul><ul><ul><ul><li>platinum -> double strand DNA damage </li></ul></ul></ul><ul><ul><ul><li>TNBC - deficiency in BRCA associated DNA repair </li></ul></ul></ul>
Byrski, JCO 2010 Neoadjuvant treatment of 102 consecutive BRCA1 (+) breast cancer pts 83% 10 12 Cisplatin 8% 2 25 AT 21% 6 28 FAC 22% 5 23 AC 7% 1 14 CMF % pCR No of pCR No treated Regimen
Platinum in TNBC <ul><li>few prospective data exist </li></ul><ul><li>metronomic cyclophosphamide and methotrexate ± cisplatin in anthracycline and taxane pretreated TNBC pts </li></ul>Bhattacharyya, ECCO 2009 12 months 16 months OS 7 months 13 months PFS 30 % 62% RR no cisplatin cisplatin
<ul><li>synthetic lethality </li></ul>PARP-inhibitors Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP DNA repair Inactive BRCA Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP Inactive BRCA cell death
PARP-inhibitors O’Shaughnessy , NEJM 2011 „ triple negative„ BC 0–2 prior chemotherapy regimens for MBC