Dados do Trabalho

Título

IS IT POSSIBLE TO ASSESS INTRINSIC AND ACQUIRED RESISTANCE TO NEOADJUVANT CHEMOTHERAPY USING A NOVEL IN VITRO BREAST CANCER CHEMORESISTANCE PLATFORM?

Introdução

Tumor resistance is the main cause of treatment failure leading to cancer progression and is classified into intrinsic (preexisting condition) and acquired resistance (induced by a drug). Some methods are available worldwide to assess drug resistance; however, no in vitro chemoresistance test is approved for clinical use in Brazil.

Objetivo

Our study aims to validate the efficacy of an in vitro chemoresistance platform to demonstrate intrinsic and acquired resistance in breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT) and analyze resistance-related genes using a machine learning and differential gene expression.

Métodos

Patients with invasive BC who underwent biopsy and who presented residual disease (RD) after NACT were included. Fresh tumor samples were collected and dissociated to obtain the tumor cells. The tumor cells were cultured in the chemoresistance platform with cytotoxic drugs (doxorubicin, epirubicin, paclitaxel, docetaxel, cyclophosphamide; carboplatin and capecitabine in selected cases), and after 72h, cell viability was evaluated. The test result is defined based on cell viability as low (< 40%), medium (40-60%), and high (> 60%) resistance. In addition, we analyze gene expression patterns and outcomes of BC patients undergoing NACT using the XGBoost and gene expression microarrays.

Resultados

Samples from 15 biopsies and 13 RD after NACT were included. Biopsy samples displayed increased rates of high resistance to docetaxel (73%) and paclitaxel (73%) compared with doxorubicin (13.3%), epirubicin (20%), and cyclophosphamide (6.6%). Five patients were referred to NACT: two patients did not respond to treatment with carboplatin and docetaxel, and the chemoresistance platform confirmed a high resistance to both drugs. The remaining three patients are currently undergoing AC-T (doxorubicin plus cyclophosphamide followed by paclitaxel) treatment, having completed the AC regimen and presenting a good clinical response. None of the tumors displayed high resistance to the drugs in the chemoresistance platform.
Most of the patients undergoing NACT received ACT + Carboplatin (69.3%), and 30.7% received docetaxel + carboplatin + anti-HER2 drugs. The chemoresistance platform revealed that RD after NACT had higher rates of drugs resistance: 100% showed high resistance to docetaxel, 92.3% to paclitaxel, 38.4% to doxorubicin, 41.6% to epirubicin, 15.4% to cyclophosphamide and 80% to carboplatin. During a median follow-up of 5 months, three patients experienced disease progression while using adjuvant capecitabine, and in the chemoresistance platform, all presented high resistance to the drug. The XGBoost algorithm and the differential gene expression found a set of genes associated with resistance, and two of them were repeated with both techniques: DIRAS3 and PELP1.

Conclusões

Our preliminary findings showed that the in vitro chemoresistance platform highlighted the involvement of intrinsic resistance in tumors with incomplete response to NACT and revealed a change in resistance profile in residual disease, potentially contributing to a worse prognosis due to acquired resistance. Machine learning and gene expression analysis identified resistance-related genes, supporting the hypothesis of intrinsic resistance in patients without a complete response to NACT.

Palavras-chave

Breast neoplasms, neoadjuvant chemotherapy, drug therapy

Financiador do resumo

Ziel Biosciences