Efficient Everolimus Treatment for Metastatic Castration Resistant Prostate Cancer with AKT1 Mutation: A Case Report.

Metastatic castration resistant prostate cancer (mCRPC), the advanced stage of prostate cancer (PCa), develops resistance to first line androgen deprivation therapy (ADT). Aberrant androgen receptor (AR) and PI3K-Akt-mTOR signaling pathway are responsible for the development and progression of mCRPC. We herein describe a case of a 64-year-old male mCRPC patient with somatic AKT1 and AR mutations. The patient, who had been heavily pretreated by ADT and AR inhibitors, showed stable disease progression when he received everolimus, an mTOR inhibitor. The PSA level dropped drastically from 1493.0 ng/mL to 237.6 ng/mL, after 3 months of treatment. The overall survival (OS) was 43 months, of which the progression-free survival (PFS) with everolimus treatment was 7 months. The administration of mTOR inhibitor, everolimus, could achieve good clinical responses along with prolonging PFS for mCRPC patients harboring AKT1 mutations. Technology in precision medicine, such as targeted next-generation sequencing (NGS) of cancer-relevant genes, has promising function in personalized therapy.

Introduction

Prostate cancer (PCa), an epithelial malignant tumor developing in the prostate, is the second most common malignant tumor among men in the world.1 Androgen deprivation therapy (ADT) via chemical or surgical castration, as the first-line treatment for metastatic PCa, can temporarily achieve good clinical responses. However, subsequent androgen deprivation resistance is widely observed in metastatic PCa patients receiving ADT, resulting in metastasis castration-resistant prostate cancer (mCRPC).2 A combination of mutated genes (such as TP53, RB1, PTEN, and BRCA1/2), activated signaling pathways (such as PI3K/AKT/mTOR, WNT/β-catenin, and SRC), and other mechanisms are involved in the progression and evolution of PCa.3 A majority of castration resistant prostate cancer (CRPC) patients are characterized with mutations and copy number alterations of genes related to the PI3K-Akt-mTOR signaling pathway,4 which plays a crucial role in castration-resistance and CRPC development.5 Clinical trials have been launched to investigate whether mTOR, pan/selective-PI3K and Akt inhibitors are novel targeted therapy agents of mCRPC.6 Everolimus (RAD001), an mTOR inhibitor, can effectively limit tumor growth via inhibiting cell proliferation, angiogenesis, and tumor cell autophagy.7 Food and Drug Administration (FDA) has approved the application of everolimus in advanced renal cell carcinoma, breast cancer, and other tumors.8 However, few case reports have clarified its role in mCRPC. Herein, we report a case of everolimus treatment against mCRPC in a patient with AKT1 and AR mutations, to provide mCRPC patients with an alternative treatment option.

Case Presentation

A 64-year-old man with a 2-year history of dysuria presented increased dysuria accompanying pain in his left leg. He was diagnosed as PCa with a high Gleason score (5 plus 3) in April 2016, by undergoing pathological tissue biopsy. His serum prostate-specific antigen (PSA) was over 100 ng/mL, and emission computed tomography (ECT) imaging showed systemic bone metastasis. Throughout the treatment period, we monitored the PSA level to evaluate the therapeutic effect (Figure 1). Prostatectomy was performed followed by 4-month flutamide (250 mg three times a day), continued goserelin (3.6 mg every 4 weeks until passing away), and 6-week chemotherapy with docetaxel (75 mg/m2 every 3 weeks) combined with zoledronic acid therapy (4 mg every 4 weeks until month 36). At the end of month 4, PSA level declined from 125.20 ng/mL to 0.02 ng/mL, and the tumor size of the lung metastasis also decreased from the whole lung to a small lesion; however, the testosterone remained at castrate level throughout the drug treatment period. From month 8 to month 14, the patient was treated with bicalutamide (50 mg once a day) as an antiandrogen drug, and the PSA level rose gradually from 0.63 ng/mL to 14.51 ng/mL. To treat against the increasing PSA, the patient received a 9-month combination treatment of abiraterone (1 g once a day) and prednisone (5 mg twice a day), during which the PSA level finally increased to 26.64 ng/mL, despite the temporary decline to 15.00 ng/mL. Although we measured a transient decrease of PSA in this period, no appreciable improvement was observed in pulmonary pathology imaging.

Figure 1

The surveillance of PSA level since initial diagnosis. The red arrow represents the prostatectomy, and the red star represents death. The online part and the line length represent the therapeutic regimen and therapy time, respectively. The PSA level at death was unknown.

The patient was then treated with docetaxel (75 mg/m2) plus prednisone (5 mg twice a day) for 5 months, carboplatin (area under the curve: 5) for 3 months, and enzalutamide (160 mg once a day) for 3 months, sequentially. The metastasis in lungs and bone kept progressing, accompanying with the increasing PSA level which reached 45.53 ng/mL, 92.07 ng/mL, and 169.6 ng/mL, respectively, after completing each of these three treatments. Based on these poor responses, olaparib (300 mg twice a day) combined with abiraterone (1 g once a day) was given to the patient for 4 months; however, PSA peaked at 1,493.0 ng/mL. Thus, tumor tissue biopsy of the right lung was sampled and performed with immunohistochemistry. Due to the positive staining results of both PSA and prostate specific membrane antigen (PSMA), we found this adenocarcinoma sample in the lung was derived from PCa. To clarify the genomic profile of tumor tissue, the lung metastasis and plasma samples underwent NGS analysis (Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China) for 425 cancer‐relevant genes. AKT1 mutation was observed in both tissue and plasma samples, while AR mutation was only detected in the tissue sample (Figure 2 and ). According to the sequencing result, oral administration of everolimus (10 mg once daily) was started and continued until passing away. After receiving this AKT1 mutation targeted treatment for 3 months, the PSA level drastically dropped from 1,493.0 ng/mL, the highest PSA level, to 237.6 ng/mL. CT imaging also revealed that the size of the lung lesion was remarkably reduced, and the size of the bone metastasis remained stable (Figure 3). In the following 3 months, PSA level remained stable, under 300 ng/mL, followed by leaping to 880.3 ng/mL. Unfortunately, the patient died in January 2020. summarizes the dosage and frequency of medication.

Figure 2

NGS analysis of the lung metastasis and plasma samples. (A) Missense mutation of AKT1 p.E17K in lung tissue and plasma samples. (B) The deletion mutation (c*612-2173+34del) of exons 5–7 and a part of exon 8 of AR in lung tissue.

Figure 3

The lung and pleural metastasis were reduced after everolimus treatment. (A) CT image of lung metastasis before medication of everolimus. Arrows represent pulmonary metastases. (B) CT image of pleural metastasis before medication of everolimus. The arrow in the lower left corner represents the pleural effusion, and other arrows represent pulmonary metastases. (C) CT image of lung metastasis after everolimus treatment for 3 months. (D) CT image of pleural metastasis after everolimus treatment for 3 months.

Discussion

ADT is the internationally recognized standard treatment for PCa.9 After 18~24 months of ADT treatment, most PCa cases irreversibly develop into mCPRC, of which the median survival time is around 1~2 years.10 Herein, we reported the treatment process of a mCRPC patient with AKT1 and AR mutations and revealed that everolimus was a potential option of limiting mCRPC progression.

This mCRPC patient successively experienced multiple approved therapies, including docetaxel, abiraterone, and enzalutamide. However, all of them yielded to unstoppable degenerative disease. Genomic profiling, using NGS, detected AR deletion and AKT1 (E17K) mutation in metastatic lung tumor tissue and plasma samples. An aberrant AR signaling pathway is widely considered as a dominant driver of PCa.11 Increased expression of androgen-synthesizing enzymes continuously sustained elevated androgen levels and contributed to AR activation.12 The detected AR deletion c.*612_2173+34del included exons 5–7 and a part of exon 8 that code for the ligand binding domain interacting with dihydrotestosterone. This deletion was very likely to be associated with AR splice variant (AR-V) of ARv567es or ARV12.13 These two types of AR-Vs were considered to be constitutively active and contribute to ADT resistance.14 Additionally, AR-Vs could not interact with heat shock protein or combine with androgen response elements in the nucleus to regular PSA expression.15 According to previous studies,16 we deduced that bicalutamide resistance was attributable to AR-Vs. Moreover, various clinical studies found that abiraterone and enzalutamide had no satisfactory long-term therapeutic effect in the mCRPC patients with AR-Vs.17 These findings could explain the high-level PSA of the patient, especially for the late stage of treatment. It was also notable that the PI3K-AKT-mTOR signaling pathway was altered in almost 100% of advanced-stage PCas.18 Many studies have revealed the abnormal activities of AKT and mTOR proteins in prostate cancer tissue, which implies the crucial role of PI3K-AKT-mTOR in the occurrence and development of PCa.19,20 The crosstalk signaling between AR and PI3K-AKT-mTOR pathways is hyperactive in mCRPC. Hence, the inhibitors of the above two pathways would produce a promising therapeutic effect in mCRPC.

Of note, AKT1 (E17K) mutations stimulate downstream signals of PI3K-AKT-mTOR that cause tumor cells to emerge transformed.21 Also, AKT1 (E17K) mutant oncoproteins can selectively destroy rare, quiescent, chemotherapy-resistant, and tumor-promoting AKT1low quiescent cancer cells (QCC).22 Multiple investigations have reported remarkably longer survival time after everolimus treatment in patients carrying AKT1 (E17K) mutations.23 Hence, we adopted everolimus to halt disease progression in this case with ADT treatment resistance. The effectiveness of everolimus could be proved by the drop of PSA level and the reduced size of lung lesion. The overall survival (OS) of this patient was 43 months, including the 7-month progression free survival (PFS) with everolimus. The patient’s OS was longer than the median OS (around 20 months) of mCRPC patient with no effective treatments.24,25 Such evidence indicated everolimus could effectively alleviate mCRPC degeneration. Some Phase II clinical trials showed that mCRPC patients did not benefit from everolimus;26,27 however, patients in these studies did not undergo genomic profiling and their AKT mutation status was unknown. Thus, our case suggested that either tumor tissue or plasma samples of mCRPC patients should be performed with comprehensive genomic profiling before being treated with targeted therapy such as everolimus.

In summary, the case report complemented the clinical application of everolimus against mCRPC. The sharply decreased PSA level was very likely to be associated with the administration of everolimus in this mCRPC patient harboring AR and AKT1 E17K mutations. He also achieved relatively good responses to everolimus, including reduced or stable tumor size of metastases, and longer PFS of 7 months. Clinical trials, enrolling patients with mutated PI3K-AKT-mTOR and AR signaling pathways, should be launched to further investigate the efficacy of everolimus in mCRPC.