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
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
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
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
(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.
Reduction of cancer related symptoms and complications
Prolongation of survival
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 .
467 cases of the international registry of lung metastases
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???
tumour burden (defined as number and site of metastases),
biological age and co-morbidities (including organ dysfunctions),
need for rapid disease/symptom control,
socio-economic and psychological factors,
and available therapies in the patient’s country (this list is not exhaustive).
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…
For pre-menopausal women, tamoxifen combined with ovarian suppression/ablation is the first choice except for tamoxifen-resistant tumors.
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 .
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
(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