Eradication of BRAF K601E Mutation in Metastatic Castrate-resistant Prostate Cancer Treated With Cabazitaxel and Carboplatin: A Case Report

Peter Steinwald,1 Elisa Ledet,1 Oliver Sartor1,2
Clinical Practice Points

Mutations in the BRAF gene are associated with a variety of human cancers. Patients with BRAF muta- tions represent a rare but clinically significant group of metastatic castrate-resistant prostate cancers, with K601E alterations being the most common type of
BRAF mutation. Limited data is available on the best course of treatment for patients with BRAF K601E prostate cancer.
Guardant 360 circulating tumor DNA (ctDNA) analysis was used to identify and monitor the presence of BRAF K601E mutation in patients with metastatic
castrate-resistant prostate cancer treated at Tulane Cancer Center. Two patients with metastatic castrate- resistant prostate cancer were found to have positive

BRAF K601E mutations. One patient exhibited an excellent response to treatment with cabazitaxel and carboplatin, which lead to the eradication of the ctDNA BRAF K601E mutation while undergoing treatment. The other patient failed treatment with abiraterone, taxotere, and a trial ERK inhibitor and passed away.
Cabazitaxel and carboplatin therapy can be used for patients with prostate cancer with BRAF K601E mu- tation. Although this report only involves 2 patients, it could be used to guide treatment for patients with
BRAF K601E prostate cancer who have failed other treatment regimens. This report also highlights the utility of ctDNA testing in guiding patient care.

Clinical Genitourinary Cancer, Vol 2019 Elsevier Inc. All rights reserved.
Keywords: mCRPC, Platinum, Precision medicine, Prostate cancer, PS

Introduction

Mutations in the BRAF gene have been linked to a variety of human cancers and may be present in 7% of cancers.1 BRAF V600E mutation1 is the most common activating mutation in BRAF. This mutation results in uncontrolled cell growth and tumorigenesis via induction of constitutive ERK signaling through hyper-activation of MAPK pathway.2 Another BRAF mutation, K601E, has been shown to be functionally similar to the V600E mutation,1 but this mutation is not directly inhibited by currently available drugs. Several drugs have been developed that target

1Tulane Cancer Center
2Hematology-Oncology Section, Department of Medicine, Tulane University School of Medicine, New Orleans, LAAddress for correspondence: Oliver Sartor, MD, Tulane Cancer Center, Tulane Uni- versity School of Medicine, 1430 Tulane Ave, SL-42, New Orleans, LA 70112

E-mail contact: [email protected]

downstream components of the MAPK pathway, such as MEK and ERK, and have been shown to be effective in treating both V600E and K601E BRAF mutations in melanoma.3,4

Analyses from cBioportal indicated that 10 (0.24%) of 4199 patients with prostate cancer had tumors with a K601E BRAF mutation. This compared with only 1 (0.024%) of 4199 with the otherwise more common V600E BRAF. In a separate analysis of patients with prostate cancer analyzed using ctDNA-derived genomic profiles, only 4 (0.0085%) of 2721 had a V600E muta- tion, whereas 12 (0.44%) of 2721 had a K601E alteration.5 Taken together, the K601E BRAF mutation, though rare, appears to be the most common BRAF activating mutation found in prostate cancer. Herein, we describe 2 cases of patients with metastatic castrate- resistant prostate cancer (mCRPC) with ctDNA BRAF K601E mutation. Both patients progressed on hormonal treatments. One patient refused further chemotherapy after receiving 6 doses of docetaxel and died. The other patient has had a prolonged and clinically meaningful response to cabazitaxel and carboplatin. In this Successful BRAF K601E Treatment Abbreviations: ctDNA ¼ circulating tumor DNA; PSA ¼ prostate-specific antigen.

report, we highlight the clinically meaningful response, given we are unaware of any similar case.

Case Report
Patient 1
A 73-year-old Caucasian male presented in April 2015 with an elevated prostate-specific antigen (PSA) of 96.1 ng/mL. Fine-needle aspiration of the left periaortic lymph node in May 2015 stained positive with PSA. Subsequent computed tomography (CT) scan revealed multi-focal lymph node and bone metastatic lesions. The patient began androgen deprivation therapy (ADT) with a GnRH agonist in July 2015, which led to a PSA nadir of 35.9 ng/mL. Abiraterone was started in November 2015 after his PSA reached a level of 82.9 ng/mL by November 2015. In December 2015, his PSA had further progressed to 254 ng/mL. Imaging at the time showed worsening of metastatic disease, and the patient was started on chemotherapy (docetaxel) at 60 mg/m2. Patient discontinued docetaxel after 3 cycles in February 2016 owing to side effects. His PSA at the time was 91.9 ng/mL. Docetaxel was restarted at 60 mg/ m2 weekly dosing in March 2016 owing to an elevated PSA of 262 ng/mL. The patient again stopped docetaxel after 3 doses in April 2016 owing to side effects. His PSA at the time was 146 ng/mL. Guardant 360 cell-free ctDNA analysis in May 2016 revealed a BRAF K601E mutation at 14.4% ctDNA with a PSA of 159 ng/ mL. The patient began a clinical trial with ulixertinib (an ERK 1/2 inhibitor) in August 2016 but discontinued the medication in October 2016 owing to side effects and spinal cord compression. His PSA progressed from 216 ng/mL to 480 ng/mL during this time, and the patient subsequently passed away.

Patient 2
A 59-year-old Caucasian male presented in 2014 with a high and rising PSA (Figure 1). Evaluation revealed metastatic disease with pulmonary nodules, abdominal and pelvic lymphadenopathy, and osseous metastatic disease in the femur, ribs, and T5 vertebrae. The
2  Clinical Genitourinary Cancer Month 2019

PSA was 155 ng/mL with a Gleason score of 9 (4 þ 5) on prostate biopsy. The patient was treated with ADT including a GnRH agonist and bicalutamide. Chemotherapy (docetaxel) was also

initiated at 60 mg/m2 on a CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) type regimen, with the dosage increased to 70 mg/m2 after the first 3-week cycle. The PSA nadir was 0.59 ng/mL and occurred approximately 6 months after initiation of ADT. Imaging studies showed a decrease in lymphadenopathy of the chest, abdomen, and pelvis, with a decrease in the number of pulmonary nodules as well. Osseous metastatic disease persisted.
PSA progression occurred 3 months after the nadir, with values rising to 2.79 ng/mL. Bicalutamide was discontinued in November 2015 with a PSA of 3.14 ng/mL. Sipuleucel-T therapy was started in December 2015 with a PSA of 3.53 ng/mL, which increased to
6.76 ng/mL in January 2016. Scans revealed progressive lymph- adenopathy and new osseous metastases.
The patient began treatment with abiraterone and prednisone in February 2016 with an initial PSA of 9.45 ng/mL, which declined to
3.97 ng/mL 1 month after treatment. Guardant 360 cell-free ctDNA analysis revealed the patient to be positive for the BRAF K601E mu- tation with 6.1% allelic fraction; the only mutation detected by ctDNA analysis at the time. Patient PSA values increased from 5.14 ng/mL to
8.85 ng/mL on abiraterone/prednisone after 2 months. Imaging showed progressive bilateral pulmonary nodules, multiple new osseous metastatic lesions, and a bladder lesion. Ulixertinib therapy began in August 2016 as part of a clinical trial, with an initial PSA of 29 ng/mL. Guardant 360 ctDNA analysis revealed the continued presence of BRAF K601E mutation at 40% circulating ctDNA along with muta- tions in the androgen receptor genes P893S and W742C at 5.6% and 1.2% ctDNA, respectively. Ulixertinib treatment was discontinued after 2 months following PSA values of 29.2 ng/mL to 63.4 ng/mL and progression of osseous metastatic disease, new bilateral pulmonary nodules, and development of mediastinal and left axillary lymphade- nopathy, as well as new liver metastasis.
Patient began cabazitaxel and carboplatin therapy in November 2016 at doses of 20 mg/m2 and an area under the curve of 4.25, respectively, with a PSA of 95.8 ng/mL. PSA values declined and reached a nadir of 0.2 ng/mL approximately 6 months after treat- ment. Repeat Guardant ctDNA analysis at the time showed no detectable levels of the BRAF K601E mutation or androgen receptor mutation. Cabazitaxel and carboplatin therapy was held in June 2017 owing to hematuria. Imaging revealed a reduction in the number of pulmonary nodules and a decrease in the size of liver metastasis and lymphadenopathy. Two months after stopping the chemotherapy, ctDNA testing in August 2017 revealed a return of the BRAF K601E mutation at 43.60% of ctDNA with a rising PSA (13.9 ng/mL). Cabazitaxel and carboplatin therapy was restarted, leading to a PSA nadir of 0.61 ng/mL approximately 4 months after treatment resumed. ctDNA testing after the second round of chemotherapy showed no detectable ctDNA levels of the BRAF K601E mutation. Cabazitaxel and carboplatin therapy was again held owing to patient hematuria. CT scan in January 2018 discovered a nodule associated with the dome of the bladder, which prompted cystoscopy and resection in February 2018 of a metastatic prostate cancer lesion. PSA value at the time was 21.4 ng/mL, and repeat Guardant testing showed a return of the BRAF K601E mutation at 49.5% of ctDNA. Cabazitaxel and carboplatin therapy was resumed in March 2018. His PSA value declined to 3.46 ng/ mL over 2 months, with no recurrence of hematuria. Guardant testing at that time had no detectable ctDNA levels of the BRAF K601E mutation.
Cabazitaxel and carboplatin was again discontinued in June 2018
owing to persistent thrombocytopenia. Abiraterone was initiated, but PSA values increased from 6.27 ng/mL to 27.8 ng/mL in July 2018. Abiraterone was discontinued, and cabazitaxel and carbo- platin therapy was restarted. In response, PSA levels again declined to a value of 5.6 ng/mL in 4 months.
Cabazitaxel and carboplatin treatment was held in November 2018 owing to urinary infections and then restarted in December 2018. CT scan showed pulmonary opacities and sclerotic lesions consistent with previous imaging. During this time period, PSA levels increased to 33.1 ng/mL. Guardant testing in December 2018 showed a recurrence of the BRAF K601E mutation at 19.5% of ctDNA prior to restarting chemotherapy. The patient remains alive in October 2019, nearly 3 years after beginning carboplatin and cabazitaxel.
Discussion
This case demonstrates the eradication, followed by recurrence, of a specific BRAF K601E mutation. During approximately 2.5 years of treatment, 25 cycles of cabazitaxel and carboplatin controlled the disease. Although the BRAF K601E mutation has

Peter Steinwald et al
previously been shown to be sensitive to ERK inhibitors in treat- ment of melanoma,2 it was not effective in these cases.
Conclusions
This is the first reported response for the BRAF K601E mu- tation to this specific treatment and may have implications for others with the same mutation. Unfortunately, we are not able to discern the reason for the response. The lack of tissue-based diagnostics is a notable weakness, but there was no doubt of the BRAF mutation’s presence given repeated presence. The
correlation of the ctDNA findings in relationship to the PSA and scans was notable.

Ethics Approval and Consent to Participate
This research is strictly retrospective and involving the collection of existing data and records. This study was approved by the Institutional Review Board of Tulane University (IRB 604170-10).

Consent for Publication
Consent for publication was obtained following Tulane Univer- sity institutional guidelines.

Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments
This study was conducted at the Tulane Cancer Center under the guidance and supervision of the Tulane University School of Medicine, including the Hematology-Oncology Section of the Department of Medicine.

Disclosure
O. Sartor discloses that he receives compensation as a consultant for Janssen, Medivation, Pfizer, and Sanofi. The remaining authors have stated that they have no conflicts of interest.

References
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