Neoadjuvant Target Therapy in Her2 Positive Breast Cancer

Neoadjuvant Target Therapy in Her-2 Positive Breast Cancer Dr. Khaled Abulkhair, Ph. D Medical Oncology SCE, Royal College, UK Ass. Professor of Clinical Oncology Mansoura University, Egypt

A long Road 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?

Pertuzumab (Neo-Sphere), 2010. 29% 45. 8 % 16. 8 %. 24% • Dual blockade is active in the neoadjuvant setting yet Chemotherapy is still the corner stone.

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

Neoadjuvant Chemotherapy - Concept developed concurrently with adjuvant chemotherapy in the 1970 s. - During the 1980 s, 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

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 T 3 disease.

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.

Adding Docetaxel…Improved c. CR…Improved p. CR…Improved RFS. . . Improved OS in p. CR

Neoadjuvant Before The Era of Targeted Therapy • Neo-Adjuvant chemotherapy adds many advantages to the management of breast cancer. • Anthracyclines are integral part in the neoadjuvant setting. • Adding Taxanes to Anthracyclines 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 HER 2 gene HER 2 –ve Growth in soft agar 225% expression of MMP-2. HER 2 +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 • Integrating Biological Agents? • Which One is The Best? • 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-2 positive 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, N 9831, BCIRG 006, Fin. HER 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 HER 1 and HER 2 tyrosine kinase. • This inhibition leads to blockade of different signaling pathways, resulting in growth arrest and/or apoptosis. • Some data indicate that lapatinib can also block HER 2 -HER 3 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 HER 2 -HER 3 dimerization. • Pertuzumab affects important signaling pathways that mediate cell proliferation and synergistically with Trastuzumab inhibits breast tumor cells survival.

Which Regimen Is The Best? • 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? • if Anthracyclines should be used or not; and if they should only be used sequentially or also concurrently with Trastuzumab? • Sequential Anthracycline - Taxanes plus Trastuzumab gives a p. CR of 40% versus 17% with chemotherapy alone. • New era began with the Dual HER-2 blockade?

Trastuzumab In The Neoadjuvant Setting • In the first reported randomized trial, Buzdar et al 2005, evaluated patients with HER 2 -positive, early-stage operable breast cancer, who were assigned to receive FECx 4 with or without Trastuzumab weekly. • Adding Trastuzumab to neoadjuvant therapy significantly increased the p. CR rate from 26. 3% to 65. 2%. • These results led to a premature closure of the study. Unfortunately, such high p. CR 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%; �� = 0. 009) and p. CR rate (43% versus 22%; �� = 0. 0007).

• The famous German (Gepar. Quattro) trial, 2010 which included 1509 patients with either locally advanced (T 3 or T 4), any hormonal status but lymph-node-positive tumours. 31%. A B EC X 4 Docetaxel (100 mg/m 2) x 4 TRASTUZUMAB For HER+++ Docetaxel (75 mg/m 2) + Capecitabine (1800 mg/m 2) x 4 S U R G E R C Docetaxel (75 mg/m 2) x 4 followed by capecitabine (1800 mg/m 2) x 4 16%. Y Trastuzumab for 1 -Year in Her-2 Positive

• (TECHNO), 2011 Taxol Epirubicin Cyclophosphamide Herceptin Ne. Oadjuvant study multicentre, prospective, open-label, phase II clinical trial enrolled 217. EC X 4 Paclitaxel 175 mg/m 2 Q 3 W + Trastuzumabx 4 Surgery Trastuzumab to complete 1 year • The primary endpoint was p. CR. • A 39 % had p. CR. With significant better 3 year DFS and OS in the group of p. CR. • A systematic review and meta-analysis, 2011 concluded that the use of Trastuzumab combined with neoadjuvant chemotherapy in patients with HER 2 -positive breast cancer seems to offer substantial benefit in terms of p. CR.

Dual Blockade in Neoadjuvant Setting (Neo-Sphere), 2010. 29% 45. 8 % 27%. 16. 8 %. 24% • Adding Pertuzumab to Trastuzumab is active and substantially increases the p. CR

Dual Blockade in Neoadjuvant Setting • (Neo. ALTTO) trial, 2012 included 455 HER 2 -positive patients who had tumours at least 2 cm in diameter. • Combination of lapatinib and Trastuzumab led to a significantly higher p. CR 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 Gepar. Quinto trial, 2012 • This randomized phase III study included 620 patients with operable or locally advanced HER 2 -positive breast cancer. • The results have confirmed a higher p. CR rate for the Trastuzumab arm (30. 3%) compared with that of lapatinib (22. 7%).

Trastuzumab plus Pertuzumab in Neoadjuvant HER 2 Positive Breast Cancer trial (TRYPHAENA), 2013. • The primary endpoint of cardiac safety was met, with a low incidence of left ventricular systolic dysfunction across all arms. • p. CR 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.

• The efficacy of p. CR as a measure of evaluating therapies for breast cancer has been a closely watched issue in oncology drug development. • In September 2013, the FDA approved an expanded indication for Pertuzumab in combination with Trastuzumab (Herceptin) and Docetaxel preoperatively in patients with high risk, HER 2 positive early stage breast cancer. • The decision marked the first time that the FDA has formally approved a neoadjuvant breast cancer treatment. • A meta-analysis by Cortazar et al, 2014 showed that achieving p. CR following preoperative chemotherapy was an especially strong predictor of event free survival in aggressive forms of breast cancer. • Attaining p. CR reduced the risk of death by 92% in cancers that were HER 2 positive and hormone receptor–negative cancers and by 84% in (TNBCs).

Comparative Effectiveness of Neoadjuvant Therapy for HER 2–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.

Value of p. CR in HER 2 -Positive Breast Cancer • Studies showed that p. CR means better DFS, OS and lower relapse rate. p. CR is considered a surrogate marker for outcome in HER-2. • However, value of p. CR differs according to the hormonal status. • The MDACC group, 2006 detected ER-negative is associated with higher p. CR rates, regardless of type and duration of chemotherapy. It is still true for target therapy too. • A recent analysis, 2011 also showed that p. CR was associated with significantly higher DFS only in hormone negative but not in hormone positive disease. • Accordingly, we have to be careful in using p. CR as a marker in the case of hormone positive Her-2 positive disease. .

Efforts to Omit Anthracyclines • Feasible and can decrease the toxicity supported by series of phase II neoadjuvant studies that reported p. CR rates ranging from 19% to 76% using Trastuzumab, a Taxanes, and a platinum compound and supported by results of TCH/DCTP. • 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.

Conclusions • HER-2 disease presents a heterogeneous group of diseases. Its management has significantly improved in recent years, and neoadjuvant treatment has become widely accepted. • Neoadjuvant Trastuzumab had a substantial impact on the outcome of this disease. • Dual blockade has revealed significant efficacy and Middle East Western presents a new therapeutic approach. Yet, cost is an important issue beside confirming OS benefits. • Guidelines for management of Her-2 positive MBC is rapidly changing due to availability of many new targeted agents e. g. TDM-1, Neratinib, Afatinib…. . • Concurrent Anthracyclines Trastuzumab looks feasible with accepted toxicity. Would this apply to Our patients?

Now, Do We Have The Fastest, Safest and Strongest? • I believe we did not reach the best yet. • How to accurately define those who will be p. CR?