Clinical Pharmacy & Pharmacogenomics Life

臨床上，一般認為，帶有 HER2-(+) 腫瘤屬於較嚴重的表現型，並代表其治療成效可能較差。

Clinically, HER2-positive tumors are associated with a more aggressive phenotype and poor outcomes.

人類上皮細胞生長因子受體 (human epidermal growth factor receptor, EGFR) 一共由四個單元組成：HER1 (又稱 EGFR), HER2, HER3 與 HER4。訊息傳遞便是藉由這些單元的兩兩偶合 (dimerization) 而產生，而偶合又可分為由不同單元異質間的偶合 (heterdimerization) 以及由相同單元組成的同質偶合 (homodimerization)。其中，HER2-HER3 的異質偶合在 PI3K–Akt–mTOR 之活化扮演了重要的角色，而此路徑與血管新生 (angiogenesis)、細胞存活、遷移 (migration)、凋亡 (apoptosis) 和增生 (proliferation) 具有極大的關係 [1-2]。

The human epidermal growth factor receptor (EGFR) family is composed of four members: HER1 or EGFR, HER2, HER3, and HER4. Signal transduction occurs as a result of receptor dimerization between members of the HER family either as heterodimerization (different receptors) or homodimerization (two of the same receptor). The HER2–HER3 heterodimer is particularly critical for activation of the phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) pathway, which in turn is able to influence other critical pathways driving angiogenesis, cell survival, migration, apoptosis, and proliferation [1-2].

隨著 trastuzumab (Herceptin®) 這個針對 HER2 之人類合成單株抗體的問世與導入治療，使 HER2-(+) 轉移性乳癌 (metastatic breast cancer) 以及早期乳癌的病人，得以有更長的存活時間 [1,3]。然而，儘管 trastuzumab 為治療帶了許多助益，但許多 HER2-(+) 的患者最終仍無可避免地死於乳癌。

With the introduction of trastuzumab, a humanized monoclonal antibody targeting HER2, significant improvements in survival were observed in patients with HER2-positive metastatic breast cancer and in patients with early-stage disease [1,3]. Despite the practice-changing impact of trastuzumab and the substantial improvement in outcomes, patients with HER2-positive metastatic breast cancer ultimately die from the disease.

Lapatinib (Tykerb®) 緊追在 trastuzumab 之後，是第二個被認證用於臨床治療的 HER2 單株抗體。Lapatinb 是一種小分子、口服生體可用率高，並能同時抑制 HER1 與 HER2 的酪胺酸激酶抑制劑 (tyrosine kinase inhibitor, TKI)，又稱 dual-kinase inhibitor。Geyer et al 的研究指出，相較於 capecitabine 單獨治療，接受 Lapatinb 與 capecitabine 合併治療的患者，病情惡化程度較慢，治療反應也較佳 [4]。Blackwell et al 對一群對 trastuzumab 治療失敗之 HER2-(+) 轉移性乳癌患者的研究發現，比起 trastuzumab 單獨治療，接受 trastuzumab 與 lapatinib 之合併治療更能提高病患的 Progression-free survival (PFS) [5]。

Beside of trastuzumab, lapatinib, an oral, small-molecule, tyrosine kinase inhibitor binding both HER1 and HER2, a dual kinase inhibitor, was the second anti-HER2 agent approved for clinical use. The combination of lapatinib and capecitabine, as compared with capecitabine alone, improved progression-free survival and the response rate (The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group) [4]. Finally, a dual targeting approach with a combination of trastuzumab and lapatinib improved progression-free survival as compared with lapatinib alone in patients with metastatic breast cancer who had not had a response to trastuzumab [5].

以治療末期或進程較快的患者來說，似乎上述治療方式都被認為是合理的，但卻也沒有任何一種治療方式是明顯較好的。目前臨床的教條是以腫瘤表現的 HER2 基因型態來決定是否投以 anti-HER2 therapy。然而，即便以這樣的治療戰略方式能為某些末期轉移患者帶來好處，但卻沒有任何方法能將其治癒。

Any of these therapeutic approaches would be considered to be appropriate for a patient with progressive disease, but there is not one approach that is convincingly superior to another, and these options can be used in sequence. The clinical dogma is to leverage the HER2 status of the tumor and continue anti-HER2 therapy, in some form, indefinitely. Although these strategies can confer benefit to some patients after disease progression, none of these strategies are curative.

Trastuzumab 在結合位是位於 HER2 的 domain IV，而 pertuzumab 則接合於 domain II [2]，使得 HER2 無法與其他 EGFR 單元偶合，從而減少其下調節活性。在單一劑量治療的表現上，pertuzumab 雖具有較低的心毒性，但其抗腫瘤活性也較和緩 [6]。而在臨床前試驗指出，pertuzumab 與 trastuzumab 似乎具有協同作用。第二期的臨床試驗發現，過去曾接受 trastuzumab 但仍持續惡化的患者，在接受二者併用之治療是有不錯的臨床成效的 [7]。近來，ENOSPHERE study 的研究結果指出，接受三重治療 (docetaxel-pertuzumab-trastuzumab) 的病人，其 pathologic complete response rate 顯著地高於 docetaxel-trastuzumab 或 docetaxel-pertuzumab 組 (45.8% vs. 29.0% and 24.0% )；而僅接受 trastuzumab-pertuzumab 治療的第四組患者，其 pathologic complete response rate 也有相當高的 16.8% [8]，顯示了對於 HER2-(+) 的患者來說，non-chemotherapy 似乎是可以被考慮的治療選擇。而在以 HER2-(+) 轉移性乳癌患者的 Phase III 隨機分派研究 (CLEOPATRA, NCT00567190) 指出，當在傳統第一線治療藥物 docetaxel-trastuzumab 加入 pertuzumab 合併治療後，可以延長六個月 PFS [9]。因此，若依 CLEOPATRA 所發表的結果來看，pertuzumab 合併 trastuzumab 與傳統化療，應能作為 HER2-(+) 轉移性乳癌患者的第一線治療。

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope of HER2 (domain II); trastuzumab binds to domain IV [2]. The binding of pertuzumab to HER2 blocks dimerization with other potential HER receptor partners, resulting in decreased downstream signaling. As a single agent, pertuzumab is associated with minimal cardiac toxic effects but only modest antitumor activity [6]. Preclinical studies showed that there was synergy between pertuzumab and trastuzumab. Phase 2 trials confirmed that the combination of trastuzumab and pertuzumab produced responses in patients who had previously had disease progression while receiving trastuzumab-based therapy [7]. More recently, the Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NEOSPHERE), showed a markedly higher pathologic complete response rate with the triple therapy of docetaxel, pertuzumab, and trastuzumab than with docetaxel and trastuzumab or docetaxel and pertuzumab. Interestingly, a fourth treatment group in the NEOSPHERE study received combination therapy with pertuzumab and trastuzumab without any chemotherapy. The antibody combination produced a pathologic complete response rate of 16.8% [8], raising the prospect of effective, nonchemotherapy approaches to HER2-positive disease if predictive markers of pathologic complete response rate could be identified. Baselga and colleagues now report the results of the Clinical Evaluation of Pertuzumab and Trastuzumab study (CLEOPATRA; ClinicalTrials.gov number, NCT00567190), a randomized, phase 3 trial in patients with HER2-positive metastatic breast cancer receiving first-line therapy with docetaxel and trastuzumab or docetaxel, trastuzumab, and pertuzumab [9]. Integrating pertuzumab into the treatment regimen improved progression-free survival by 6 months. On the basis of the data from the CLEOPATRA trial, pertuzumab would logically be used in combination with trastuzumab and chemotherapy as first-line therapy of HER2–positive metastatic breast cancer.

免疫共軛製劑 (immunoconjugate agent) － Trastuzumab-maytansine (DM1) (TDM1; Genetech) 是將 DM1 這種抗微管細胞毒殺製劑 (antimicrotubule cytotoxic agent) 與 trastuzumab 共軛結合的新型藥物。由於利用 trastuzumab 的標靶特性，DM1得以更準確的執行毒殺癌細胞作用，也因此對正在接受 anti-HER2 therapy 與傳統化療的 HER2-(+) 轉移性乳癌末期患者具有顯著的治療效果 [10]。目前，以曾接受 trastuzumab 之 HER2-(+) 轉移性乳癌病患為受試者的大型隨機分配 phase III 臨床試驗 (EMILIA, NCT00829166) 正在進行中，預期將比較 TDM1 與 capecitabine-lapatinib 之治療效果。

Trastuzumab–maytansine (DM1) (TDM1; Genentech) is an immunoconjugate agent that combines trastuzumab with DM1, an antimicrotubule cytotoxic agent. TDM1 has significant antitumor activity in patients with HER2-positive metastatic breast cancer who had progressive disease while they were receiving anti-HER2 therapy and chemotherapy [10]. A large, randomized, phase 3 clinical trial (EMILIA, NCT00829166) is comparing TDM1 with capecitabine–lapatinib in patients with HER2-positive metastatic breast cancer who have received pretreatment with trastuzumab. Smaller phase 2 trials have also shown the antitumor activity and acceptable side-effect profile of pertuzumab TDM1 therapy (NCT00875979 and MARIANNE, NCT01120184).

其他仍有許多口服小分子的 TKI 陸續被開發中，如 Afatinib (BIBW 2992; Boehringer Ingelheim)，是一不可逆結合於 EGFR (HER1), HER2 與 HER4 的口服 TKI。初期報告指出，afatinib 無論是單用或是合併化療治療，在接受過 anti-HET2 therapy 的末期乳癌患者中都具有抗癌活性 [11]。

Several oral, small-molecule, tyrosine kinase inhibitors are also in development. Afatinib (BIBW 2992; Boehringer Ingelheim) is an oral, irreversible HER family inhibitor targeting EGFR (HER1), HER2, and HER4. Initial reports confirm the antitumor activity of afatinib alone or with chemotherapy in patients who have had disease progression while they were receiving other anti-HER2 therapy [11].

另一個對 EGFR (HER1), HER2 與 HER4 具有不可逆抑制效果的口服 TKI 是 Neratinib (HKI-272; Pfizer & Puma Biotech)，此品初步報告指出，不管是否曾接受過 trastuzumab 的病人服用此品，都具有抗癌活性 [12]。

Neratinib (HKI-272; Pfizer and Puma Biotech) is an oral, irreversible inhibitor of EGFR (HER1), HER2, and HER4 that has shown substantial single-agent activity in patients who have never received treatment with trastuzumab, as well as in patients who have already received trastuzumab therapy [12].

雖然，HER2-(+) 的乳癌患者只占全部的 25-30%，但是這一類藥物的開發與現世無疑地帶給這些患者一線曙光，但也成為臨床醫師在選擇治療方向時的挑戰。而這些挑戰也將持續反應在未來的研究上，並期望能幫助我們在面對其他型態的乳癌時，能有個好的治療策略。

Although HER2-positive breast cancer accounts for only 25 to 30% of breast cancers, the increasing therapeutic options provide hope to patients and considerable challenges for clinicians. For patients with metastatic breast cancer who have progressive disease, there may be numerous anti-HER2 agents available that could be used in combination or in sequence. These are challenges that reflect the rewards of successful translational research, challenges we hope to face with other subsets of breast cancer.

Reference:

1. Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med 2005;353: 1734-6.

2. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB-pertuzumab complex. Cancer Cell 2004;5: 317-28.

3. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N  Engl J Med 2001; 344: 783-92.

4 Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43. [Erratum, N Engl J Med 2007;356:1487.]

5. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010;28: 1124-30.

6. Gianni L, Lladó A, Bianchi G, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor2-negative metastatic breast cancer. J Clin Oncol 2010;28:1131-7.

7. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010;

28:1138-44.

8. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(1): 25-32

9. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2011. DOI: 10.1056/NEJMoa1113216.

10. Burris HA III, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;29: 398-405.

11. Hickish T, Whitley D, Lin N, et al. Use of BIBW 2992, a novel irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor to treat patients with HER2-positive metastatic breast cancer after failure of treatment with trastuzumab. Cancer Res 2009;69:Suppl 3: 5060. abstract.

12. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2010;28: 1301-7.

Wind Wei-Lun Chang

2012.01.05