Tesis

Ekspresi P-glycoprotein dan Respons terhadap Kemoterapi Neoajuvan pada Kanker Payudara Lanjut Lokal: Studi Kohort Prospektif Multisentra = P-glycoprotein Expression and Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer: Multicenter Prospective Cohort Study.

Kemoterapi neoajuvan (KNA) merupakan salah satu modalitas terapi pada kanker payudara lanjut lokal (KPD-LL). Beberapa studi telah menunjukkan KNA dapat meningkatan kesintasan keseluruhan bila didapatkan respons patologis komplet, namun efektifitasnya dihambat oleh kemoresistensi yang dapat dimediasi oleh P-glycoprotein (Pgp). Terhadap korelasi tersebut, hasil dari studi-studi terdahulu saling kontradiktif. Meskipun demikian, di Indonesia, dimana mayoritas pasien dengan kanker payudara datang dalam stadium lanjut lokal, investigasi mengenai ekspresi Pgp dan korelasinya dengan respons terhadap KNA belum pernah dilakukan. Tujuan dari studi ini adalah untuk mengkaji hubungan antara ekspresi Pgp dengan respons terhadap KNA pada pasien KPD-LL. Studi kohort prospektif multisentra dilakukan di RSUPN Dr. Cipto Mangunkusumo dan RSUD Koja pada periode September 2018 sampai Mei 2019. Dilakukan consecutive sampling terhadap subjek dengan KPD-LL pada periode waktu tersebut. Analisis imunohistokimia dilakukan pada sampel biopsi untuk menilai ekspresi Pgp secara semikuantitatif. Respons klinis dinilai pascakemoterapi cyclophosphamide 600 mg/m 2 , doxorubicin 50 mg/m 2 , and 5-fluorouracil 600 mg/m 2 (CAF) tiga siklus dengan menggunakan kriteria WHO. Subjek yang dinilai operabel pascaKNA menjalani operasi mastektomi radikal modifikasi. Respons patologis dinilai pada spesimen bedah dengan menggunakan kriteria Miller-Payne. Sebanyak 30 subjek laik dan bersedia masuk ke dalam penelitian. Namun, tiga subjek dieksklusi karena loss to follow-up. Usia rerata subjek penelitian adalah 46,2±9,6 tahun dengan sebagian besar kasus merupakan duktal invasif (77,8%) dan subtipe luminal B (61,1%). Pgp positif pada 21/27 subjek (77,8%) dan lemah/negatif pada 6/27 subjek (22,2%). Respons klinis didapatkan pada subjek dengan Pgp positif dan negatif, sebanyak 61,9% dan 66,7%. Respons patologis komplet hanya didapatkan pada satu pasien dengan Pgp negatif. Tidak ada perbedaan antara subjek dengan Pgp positif dan Pgp negatif dalam hal respons klinis (RR 1,1, IK 95% 0,33-4,01, p = 0,61) maupun respons patologis (RR 1,3, IK 95% 0,8-1,9, p = 0,22). Hasil studi ini menunjukkan bahwa mayoritas pasien KPD-LL mengekspresikan Pgp, namun Pgp tidak dapat digunakan sebagai prediktor respons terhadap KNA, baik klinis maupun patologis. Meskipun demikian, tidak adanya standar pengukuran Pgp harus dipertimbangkan dalam menginterpretasikan hasil penelitian. Diduga hal tersebut berkontribusi terhadap hasil yang saling kontradiktif pada penelitian-penelitian terdahulu. Dibutuhkan studi lanjutan untuk membuat standar pemeriksaan Pgp disertai pemeriksaan fungsional untuk menjawab permasalahan ini.
Kata Kunci: Kanker payudara lanjut lokal, kemoterapi neoajuvan, P-glycoprotein, respons klinis, respons patologis


Neoadjuvant chemotherapy (NACT) is one of the modalities used to treat locally advanced breast cancer (LABC). Studies have shown that it can improve overall survival if pathological complete response is achieved, but its efficacy is impeded by chemoresistance of which can be mediated by P-glycoprotein (Pgp). Numerous studies show contradictory results regarding this correlation. Nevertheless, in Indonesia, where the majority of breast cancer patients come in locally advanced stage, an investigation on Pgp expression and its correlation with response to NACT has not been done. The aim of this study is therefore to explore the association between Pgp expression and response to NACT in LABC patients. A multicenter prospective cohort study was carried out in Dr. Cipto Mangunkusumo General Hospital and Koja General Hospital from September 2018 to May 2019. Subjects with LABC were sampled consecutively within this timeframe. Immunohistochemical analyses of the biopsy samples were done to semiquantitatively measure Pgp expression. Clinical response was evaluated after three cycles of cyclophosphamide 600 mg/m 2 , doxorubicin 50 mg/m 2 , and 5-fluorouracil 600 mg/m 2 (CAF) NACT using WHO response criteria. Subjects, who were deemed operable postNACT, underwent modified radical mastectomy. Afterwards, the surgical specimens were evaluated for pathological response following Miller-Payne criteria. Thirty subjects were eligible and willing to participate in the cohort. However, three subjects were excluded due to lost to follow-up. Mean age of the subjects was 46.2±9.6 years old, and most of the cases were ductal invasive (77.8%) and luminal-B subtype (61.1%). Pgp was strongly expressed in 21/27 subjects (77.8%) and weak/negative in 6/27 subjects (22.2%). Clinical response was observed in both Pgp positive and negative to be 61.9% and 66.7% subjects, respectively. pCR was seen only in one Pgp negative subject. There was no difference between Pgp positive and negative subjects in terms of clinical response (RR 1.1, 95% CI 0.33-4.01, p = 0.61) and pathological response (RR 1.3, 95% CI 0.8-1.9, p = 0.22). The results show, Pgp is expressed in the majority of LABC patients, but it cannot be used as a predictor of response to NACT, either clinically or pathologically. However, the fact that there is no standard of Pgp measurement must be taken into consideration when interpreting these results. It is suspected that this issue contributes to the conflicting results reported in previous publications. Further studies with the establishment of a standardized method of Pgp measurement coupled with a functional assay is warranted to elucidate this matter.
Keywords: Locally advanced breast cancer, neoadjuvant chemotherapy, P-glycoprotein, clinical response, pathological response