Benefit of everolimus as a monotherapy for a refractory breast cancer patient bearing multiple genetic mutations in the PI3K/AKT/mTOR signaling pathway

Abstract

A postmenopausal patient with a diagnosis of estrogen receptor (ER) (+), progesterone receptor (PR) (+), and human epidermal growth factor receptor-2 (HER2) (-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient's tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases (PI3K) signaling pathway were detected via next-generation sequencing (NGS)-based liquid biopsy, including a p. G1007R missense mutation in exon 21 of PIK3CA (33.61%), a p.L70fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten (PTEN) (49.14%), and a p. D1542Y missense mutation in exon 32 of mammalian target of rapamycin (mTOR) (1.66%). Therefore, only the mTOR inhibitor everolimus was administered to the patient. Partial remission (PR) was observed after 2 months, and sustained stable disease (SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3CA decreased to 4.17%, and that the PTEN and mTOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3K/ARK/mTOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.

Keywords: Breast cancer; PI3K/AKT/mTOR; everolimus; liquid biopsy; next-generation sequencing.

1

Microscopic images of circulating tumor cells (original magnification ×100). Anti-EpCAM was used to capture the cells. Arrows refer to the circulating tumor cells in 2 mL of peripheral blood that tested positive for CK (green) and DAPI (blue) and negative for CD45 (orange). (A) Circulating tumor cells were not detected in the control patient. (B–D) A total of 31 circulating tumor cells were observed in the patient, which suggested a heavier tumor burden.

2

Images of primary and metastatic lesions on the aortic arch level during the period of disease surveillance. (A) Enhanced computed tomography upon admission showed massive cancerous nodes, and the largest one was 8.9 cm × 5.3 cm in size, which is accompanied by multiple lymphadenectasis and severe edema. (B) After 2 cycles of ET regimen chemotherapy, the patient was stable based on the evaluation via CT (7.1 cm × 4.0 cm) on December 2015. (C) After 2 months of treatment with everolimus, a remarkable remission of the primary lesion (2.8 cm × 2.2 cm) and metastatic lymph node was observed via CT on April 2016, and the clinical response reached PR. (D-G) CT images obtained on August 2016, December 2016, April 2017, and August 2017 showed that the tumor size decreased, and the patient was in stable condition. All therapeutic effect evaluations were carried out according to the RECIST criteria.

3

Changes in the indicators during the disease course. (A) The level of tumor markers was extremely high upon admission, decreased rapidly, and remained at a low level after everolimus treatment since February 16, 2016. CA15-3, CEA and CA125 decreased significantly after the treatment of everolimus (P<0.001,P<0.01,P<0.05). The detectable upper limit of CA15-3 is 300 U/mL, which means more than or equal to 300 U/mL on the graph. (B) The left part presents the condition of the patient before the treatment, with axillary metastatic nodules accompanied by extensive skin infiltration and ulcer. After everolimus treatment, the metastatic nodules disappeared, and the ulcer has healed as shown in the right picture. *P<0.05, **P<0.01, ***P<0.001