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Neoadjuvant Therapy in Her-2 Positive Breast Cancer Dr. Khaled Abulkhair, PhD Medical Oncology SCE, Royal College, UK Ass. Professor of Clinical Oncology Mansoura University, Egypt Questions? 1. Is systemic therapy needed in breast cancer? 2. Adjuvant or Neoadjuvant? 3. What is the best Chemotherapy? 4. Why Her-2 disease is a unique subtype?. 5. How to target Her-2 positive breast Cancer? 6. New perspectives? Why To Offer Chemotherapy? • 35% to 85% of patients with lymph node-positive breast cancer will develop metastatic disease. • A review of the literature suggests that even small (<1 cm), node-negative tumors have reported recurrence rates ranging up to 20% by 10 years. • The 1990 NIH consensus conference recommended the routine administration of adjuvant systemic therapy to women with high-risk histologically negative axillary nodes based on newer data. • WHAT IS THE BEST CHEMOTHERAPY? Searching For The Best….is a Continuous Efforts Every time they give us a car we believe it is the Safest, Fastest, and Strongest? MTX…1951 Anthracycline…1990 CMF…..1973 Taxanes…Late Nineties Short Messages About Adjuvant Chemotherapy For Breast Cancer Review of the serial reports of the EBCTCG's metaanalyses. 1. Chemotherapy reduces the risk of recurrence and death. 2. Combination is more effective than single-agent . 3. Chemotherapy is more effective for women younger than 50 years of age than for older women. 4. Anthracyclines-containing regimens are more effective. 5. Six months of chemotherapy considered optimum. 6. Addition of Taxanes significantly improves RFS and OS. Neoadjuvant Chemotherapy - Concept developed concurrently with adjuvant chemotherapy in the 1970s. - During the 1980s, several randomized and non-randomized studies were conducted to evaluate the worth of preoperative chemotherapy for operable breast cancer. - All of these studies demonstrated that preoperative chemotherapy results in a high rate of primary tumor response Advantages of Neoadjuvant Chemotherapy • • • • Facilitates mastectomy in operable disease. Increases rates of BCS for larger primary tumors. Allows in-Vivo Monitoring the response to chemotherapy. The pathological response of disease to neoadjuvant chemotherapy is prognostic. An invaluable research tool to: - Directly compare the effectiveness of two systemic regimens - Directly study biological factors that influence chemotherapy sensitivity/resistance • Identify patients for trials of new agents because of their high risk for recurrence despite receiving the best treatment. Potential Disadvantages Information concerning the pathological extent of disease prior to treatment is unknown. Accordingly, the following are less certain: - Margin status of a BCS? - Risk of additional lymph node disease when a sentinel lymph node is negative or shows fibrosis and/or treatment-induced changes - Indications for post-mastectomy radiation Adjuvant OR Neoadjuvant • Does the patient desire breast preservation? • Is there a benefit from knowledge of in-vivo chemosensitivity? To investigate this, the NSABP and EORTC independently conducted clinical trials that compared neoadjuvant chemotherapy with adjuvant chemotherapy for patients with stage II or III disease. - Data published 2001, Both trials found that BCS rates were higher (22% BCS rate vs 8%) in the neoadjuvant arm due to down-staging of T3 disease. NSABP B-18 Trial: Schema Operable Breast Cancer •Stratification • Age • Clinical tumor size • Clinical node status Operation AC x 4 + TAM if >50 yrs. AC x 4 + TAM if >50 yrs. Operation Un-answered question ….the need for further therapy following initial treatment? Many trials have been launched: • the Aberdeen trial • M. D. Anderson Trial 85-01 • NSABP protocol B27 published 2005. NSABP B-27: Determining the effect of combining Docetaxel with preoperative AC Does the addition of Docetaxel to preoperative AC affect response rates, DFS and OS? Patients with primary operable ANY T SIZE breast cancer; HER2 status not defined (N=2404) AC q3w x 4 cycles Surgery AC q3w x 4 cycles Docetaxel 100 mg/m2 q3w x 4 cycles Surgery Surgery Docetaxel 100 mg/m2 q3w x 4 cycles AC q3w x 4 cycles Tamoxifen was initiated concurrently with chemotherapy Bear H, et al. 2006 Rastogi P, et al. 2008 Adding Docetaxel…Improved cCR…Improved pCR…Improved RFS...Improved OS in pCR Emerging lessons from NSABP B-27 Trial • In spite lack of OS benefits, yet presence of better R.R, higher BCS, improved RFS and in vivo assessment of chemotherapy all favour Neoadjuvant. • pCR linked to better OS. • Assessing the response permits the activity of different Chemotherapy regimens to be more easily compared. • Response data can also provide insights into the biological determinants of Chemotherapy response. Weekly paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) paclitaxel followed by FAC- final results of a prospective phase III randomized trial. By Hortobagi et al. Proc Am Soc Clin Oncol 21: 2002 (abstr 135) • Pathologic Complete Remission Rates (Breast and Lymph Nodes) : Weekly vs. Q 3 Week Paclitaxel Node Positive Weekly (n = 50) Q 3 Week (n= 51) (n = 67) pCR 14 (28%) 7 (13.7%) Node Negative Weekly (n = 68) Q 3 Week 20 (29.4%) 9 (13.4%) Weekly Paclitaxel is superior to q 3 weeks. Neoadjuvant Before Targeted Therapy • Neo-Adjuvant chemotherapy adds many advantages to the management of breast cancer. • Anthracyclines are integral part in the neoadjuvant setting. • Adding Taxanes boosts both DFS and OS. • Weekly Paclitaxel is preferred over Q 3 weeks. Effect of HER-2 amplification on breast cancer cells (Sinn, 1990). Human breast cancer cells DNA synthesis 50–75% Cell growth rate 30–50% MCF-7 Transfect with MCF-7 Growth in soft agar 225% HER2 gene expression of MMP-2. HER2 –ve HER2 +ve Transformed Aggressive phenotype Metastatic potential 220% in nude mice HER-2 Oncogene: overexpressed in 20-25% of breast cancers.. Tissuespecific expression of myc, ras, and HER-2 in mammary glands of transgenic mice has been shown to result in an increased incidence of both benign and malignant breast pathology (Sinn, 1990). Biological Target…Her- Family A New Story Began Searching for optimum Neo-Adjuvant Therapy in Her -2 Positive Breast Cancer • What is the optimum Chemotherapy? • What is the optimum Targeted Therapy? • Did we reach the best available treatment? Trastuzumab ..…The Gold Standard Fast Trip from metastatic to neoadjuvant Trastuzumab • Trastuzumab is a humanized recombinant monoclonal antibody directed against HER-2 receptors. • According to the international panel on neoadjuvant therapy, it should be part of the neoadjuvant treatment regimen in patients with HER-2positive breast cancer. • Many studies have shown that blockade of these receptors has therapeutic implications (Zhang et al., 1999). • Furthermore, these antibodies have synergistic interactions with cytotoxic agents, such as the anthracyclines, the platinum analogs, and the taxanes (Baselga et al., 1994). • Trastuzumab in the adjuvant setting produced spectacular results with about 50% decrease in recurrence as shown in 6 randomized trials. • After follow-ups ranging from 1 to 2 1/2 years, five trials (NSABP B- 31, N9831, BCIRG006, FinHER and HERA) demonstrated such marked benefit that the trials were stopped and the results reported. • Trastuzumab-treated patients had about a 46% to 58% reduction in risk of recurrence in these five trials. • Significant survival benefits have emerged in five of the six trials, with a 33% to 59% reduction in mortality. Lapatinib • Lapatinib is an orally active, small molecule which reversibly inhibits HER1 and HER2 tyrosine kinase. • This inhibition leads to blockage of different signaling pathways, resulting in growth arrest and/or apoptosis. • Some data indicate that lapatinib can also block HER2-HER3 mediated cell growth [22, 23]. • Lapatinib as a small molecule can penetrate the blood-brain barrier and, therefore, was claimed for therapy and prevention of brain metastases. Pertuzumab • Pertuzumab is the humanized monoclonal antibody that binds to dimerization domain II of HER-2 receptor, which is necessary for HER-2 activation and cell signaling. • Clinically, the most important action of Pertuzumab is inhibition of HER2-HER3 dimerization. • Pertuzumab affects important signaling pathways that mediate cell proliferation and synergistically with Trastuzumab inhibits breast tumor cells survival. Which Regimen Is The Best? • Currently, I do not know the exact answer to this question. A number of chemotherapy + Trastuzumab combinations have proven good response rates with good tolerability. However, several aspects have yet to be clearly defined: • Which regimen has superior efficacy; how long the neoadjuvant therapy should last; if Anthracyclines should be incorporated or not; and if they should only be used sequentially or also concurrently with Trastuzumab? • Sequential Anthracycline - Taxanes plus Trastuzumab gives a pCR of 40% versus 17% with chemotherapy alone . • New era began with the Dual HER-2 blockage? Trastuzumab In The Neoadjuvant Setting • In the first reported randomized trial, Buzdar et al 2005, evaluated patients with HER2-positive, early-stage operable breast cancer, who were assigned to receive FECx4 with or without Trastuzumab weekly . • Adding Trastuzumab to neoadjuvant therapy significantly increased the pCR rate from 26.3% to 65.2%. • These results led to a premature closure of the study . Unfortunately, such high pCR rates have not been observed in successive trials. • The Neoadjuvant Herceptin (NOAH) trial, 2010, found that adding Trastuzumab significantly improved overall response rate (ORR) (87% versus 74%; 𝑃 = 0.009) and pCR rate (43% versus 22%; 𝑃 = 0.0007). • The famous German (GeparQuattro) trial, which included 1509 patients with either locally advanced (T3 or T4), any hormonal status but lymph-node-positive tumours. A Docetaxel (100mg/m2) x4 S U B EC X 4 R Docetaxel (75mg/m2) + Capecitabine (1800mg/m2) x4 G E R C Docetaxel (75mg/m2) x4 followed by capecitabine (1800mg/m2) x4 Y Trastuzumab for 1-Year in Her-2 Positive - pCR was doubled in HER-2 positive patients compared to the HER2- negative group (31.7% versus 15.7%). - In the HER2-positive group, a pCR was observed in 48 (32.9%) first arm, 45 (31.3%) second arm, and 47 (34.6%) the third arm. - Even in case of irresponsiveness to EC therapy, the pCR rate was higher in the HER2-positive. • (TECHNO), 2011 Taxol Epirubicin Cyclophosphamide Herceptin NeOadjuvant study multicentre, prospective, open-label, phase II clinical trial enrolled 217. EC X 4 Paclitaxel 175 mg/m2 Q3W + Trastuzumabx4 Surgery Trastuzumab to complete 1 year • The primary endpoint was pCR. • A 39 % had pCR. With significant better 3 year DFS and OS in the group of pCR. • A systematic review and meta-analysis, 2011 concluded that the use of Trastuzumab combined with neoadjuvant chemotherapy in patients with HER2-positive breast cancer seems to offer substantial benefit in terms of pCR. Dual Blockage in Neoadjuvant Setting • (NeoALTTO) trial, 2012 included 455 HER2-positive patients who had tumours at least 2 cm in diameter . • Combination of lapatinib and Trastuzumab led to a significantly higher pCR rate (51.3%) than that of the monotherapy arms. The response to lapatinib was numerically lower than to Trastuzumab, although the difference did not reach statistical significance. • The dual combination was associated with higher toxicity, especially diarrhoea and hepatotoxicity, and more patients discontinued therapy because of adverse events. The comparison of Lapatinib versus Trastuzumab was the aim of the GeparQuinto trial, 2012 • This randomized phase III study included 620 patients with operable or locally advanced HER2-positive breast cancer. • The results have confirmed a higher pCR rate for the Trastuzumab arm (30.3%) compared with that of lapatinib (22.7%). Pertuzumab (Neo-Sphere), 2010. 29% 45.8 % 16.8 %. 24% • Dual blockade is active yet Chemotherapy is still a corner stone. Trastuzumab plus Pertuzumab in Neoadjuvant HER2Positive Breast Cancer trial (TRYPHAENA), 2013. Note first to omit Anthracyclines • The primary endpoint of cardiac safety was met, with a low incidence of left ventricular systolic dysfunction across all arms. • pCR rates were similar across the three arms and regardless of the chemotherapy chosen reached from 57% to 66% with DCTP. Better results were seen in patients with hormonenegative disease. Comparative Effectiveness of Neoadjuvant Therapy for HER2–Positive Breast Cancer: A Network Meta-Analysis • In a recent meta-analysis published JNCI J Natl Cancer Inst (2014). • Evaluating a total of 10 eligible trials including 2247 patients in seven different treatment arms were assessed. Chemotherapy +\- Anti-HER-2 agents that included Trastuzumab, Lapatinib, and Pertuzumab. • This study indicates that combining two anti-HER-2 agents with Chemotherapy is the most effective treatment modality in the neoadjuvant setting for HER-2 positive breast cancer. pCR in HER2-Positive Breast Cancer • Studies showed that pCR means better DFS, OS and lower relapse rate. pCR is considered a surrogate marker for outcome in HER-2. • However, value of pCR differs according to the hormonal status. • The MDACC group, 2006 detected ER-negative disease is associated with higher pCR rates, regardless of type and duration of chemotherapy. • A recent analysis, 2011 also showed that pCR was associated with significantly higher DFS only in hormone negative but not in hormone positive disease. • Accordingly, we have to be careful in using pCR as a marker in the case of triple-positive tumors. Efforts to Omit Anthracyclines • Several phase II trials have been reported to date in which Anthracycline was substituted with carboplatin, based on preclinical data suggesting synergy between Trastuzumab, a Taxanes, and a platinum compound and supported by results of TCH. • A series of phase II neoadjuvant studies reported pCR rates ranging from 19% to 76%. • TRYPHAENA supported omitting Anthracyclines. • However, the BCIRG 006 study demonstrated in the adjuvant setting a slightly inferior disease-free survival for the TCH against ACTH regimen. New Approaches • HER2 can stimulate angiogenesis through vascular endothelial growth factor up-regulation. Therefore, HER2 blockage, together with inhibition of angiogenesis, could be another treatment option. • In phase II study, 2011, neoadjuvant therapy with nab-paclitaxel, carboplatin and Bevacizumab led to a pCR rate comparable to that found in chemotherapy/Trastuzumab combinations Conclusions • HER-2 positive breast cancer presents a heterogeneous group of diseases with various biological characteristics. • Management of patients with this type of breast cancer has significantly improved in recent years, and neoadjuvant treatment has become widely accepted. • The introduction of Trastuzumab to Neoadjuvant setting has brought important progress in the treatment of HER-2 positive breast cancer. • All breast cancers are not the same, so it makes sense that treatment can no longer be one-size-fits all. • Nowadays, sequential Anthracycline-Taxanesbased chemotherapy in combination with Trastuzumab is considered the best-studied therapy for HER-2 positive breast cancer in the neoadjuvant setting. • The dual blockage of HER-2 receptor has revealed significant efficacy and presents a new therapeutic approach. Yet, cost is an important issue beside confirming OS benefits on follow up. Now, Do We Have The Fastest, Safest and Strongest? • I believe we did not reach the best yet. • What are the reliable biomarkers for anti-HER2 therapy?….How to define those who will be pCR?