|LETTER TO EDITOR
|Year : 2021 | Volume
| Issue : 2 | Page : 417-419
Comprehensive molecular profiling: The saga of mutations and novel therapeutics
MBA Pharmaceutical Management, School of Business Management, NMIMS, Narsee Monjee Institute of Management Studies, SBM, Mumbai, Maharashtra, India
|Date of Submission||02-Apr-2021|
|Date of Decision||06-Apr-2021|
|Date of Acceptance||07-Apr-2021|
|Date of Web Publication||30-Jun-2021|
I-2301, Ravi Estate, Thane West, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mohan T. Comprehensive molecular profiling: The saga of mutations and novel therapeutics. Cancer Res Stat Treat 2021;4:417-9
The advent of various molecular profiling techniques has led to great success in identifying gene mutations and rearrangements that can lead to tumor formation in an individual. At times, anti-cancer treatments cause the tumor to shrink. However, the tumors usually relapse because of the flagrant tendencies of the mutations caused by certain drugs, despite a well-planned treatment regimen.
Kapoor et al. in their article titled, “Molecular Tumor Board: Case 4 Salivary Gland Cancer: Novel therapeutic options as a result of comprehensive molecular profiling,” have described a case of salivary duct carcinoma (SDC) arising from the parotid swelling. The tumor was found to be androgen receptor (AR)-positive but human epidermal growth factor receptor 2 negative. Based on the pathological findings, the patient was started on hormonal therapy with leuprolide and bicalutamide, which are also used in the treatment of prostate cancer. However, after 3 months of treatment, there was an increase in the tumor size, due to which the treatment plan was changed, and the patient was started on paclitaxel and carboplatin on a weekly basis.
The patient's biopsied tissue was analyzed using the next generation sequencing (NGS) and the tumor was found to harbor a BRAF V600E mutation. As a result, the patient's treatment regimen was changed to dabrafenib and trametinib, which inhibit the BRAF and MEK 1/2 kinases, respectively. These were tolerated well by the patient, with disease stabilization. However, after 5 months, new skin nodules were observed on the patient's neck and upper chest wall, and further tests revealed a high-grade cancer.
I believe that an NGS analysis could have been done initially when the patient tested AR-positive or a real-time polymerase chain reaction (PCR) could have been performed for the detection of the AR splice variant 7 (AR-V7). Even though NGS is expensive, it could have helped in the early detection of mutations in the patient's tumor. This could have prevented the stress from repeat biopsy and improved the patient's access to targeted therapy right from the beginning.
Several studies have reported that AR-V7 plays an important role as a biomarker to predict the lack of response to AR-targeted therapies or androgen deprivation therapy (ADT), owing to the lack of a ligand-binding site on AR-V7. This has been previously reported in metastatic castration-resistant prostate cancer and even in SDCs. Yang et al. reported that there was an over-expression of AR-V7, a constitutively active splice variant of AR, at both transcript and protein levels in ADT-naïve SDCs. Interestingly in this study, they observed and validated the expression of AR-V7 in patients with SDC without prior exposure to ADT. AR-V7 can be detected using immunohistochemistry and reverse transcription PCR techniques.
Before treatment onset, magnetic resonance imaging showed the presence of a hypointense lesion completely involving the superficial and deep lobes of the left parotid gland, with widening of the left stylomandibular foramen and perineural spread along the facial nerve. In addition, the left paraspinal muscle was also involved, making the tumor unresectable as mentioned by the authors. However, the nodal status and distant metastasis of the tumor have not been commented upon. This could have helped the readers comment on the decision of elective neck dissection or therapeutic (or selective) neck dissection of the cervical lymph nodes. Lin et al. in their article described a similar case, where the patient underwent direct laryngoscopy with biopsy, followed by a left modified radical neck dissection and left total parotidectomy.
Pandey et al. in their article on novel therapeutic options for salivary gland tumors reviewed the ongoing trials and reported that chemotherapy as well as targeted therapy are viable options for the treatment of these tumors depending upon the histology and molecular biomarkers.
There were certain noteworthy points mentioned in a paper by Byrd and Morris that parotid tumors with facial paralysis and lymphovascular invasion may also have a higher rate of occult lymph node metastases. In addition, they mentioned that the site of primary tumor is a prognostic marker for lymph node involvement in salivary gland carcinomas, with lymph node involvement noted in 25% of parotid gland and 42% of submandibular gland malignancies.
Moreover, in case of parotid tumors, radiation to the neck has been shown to have similar benefit in regional control as therapeutic neck dissection. If gross regional disease is present, neck dissection followed by radiation should be performed, and in cases of clinically evident parotid metastases, therapeutic neck dissection should generally be included with parotidectomy. This can help to control the spread of the tumor to some extent but may cause other morbidities to the patient.
The authors have mentioned that the presence of a BRAF V600E mutation may be associated with an entirely different clinical interpretation in tumors other than melanomas. Therefore, I would urge them to assess the potential of encorafenib in adenocarcinomas of the oral cavity harboring a BRAF V600E mutation with hormone therapy in patients without AR-V7 and taxane-based therapy in patients with AR-V7. With regard to the treatment regimen planned for the patients with AR-V7., and the trials conducted, it is unclear as to why clinicians do not opt for encorafenib (BRAF kinase inhibitor) along with trametinib, binimetinib, selumetinib, and cobimetinib for the treatment of SDCs.,
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kapoor A, Noronha V, Chougule A, Chandrani P, Shetty O, Patil VM, et al
. Molecular tumor board: Case 4 Salivary Gland Cancer: Novel therapeutic options as a result of comprehensive molecular profiling. Cancer Res Stat Treat 2020;3:554-63. [Full text]
Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: Structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin 2015;36:3-23.
Yang RK, Zhao P, Lu C, Luo J, Hu R. Expression pattern of androgen receptor and AR-V7 in androgen-deprivation therapy-naïve salivary duct carcinomas. Hum Pathol 2019;84:173-82.
Lin VT, Nabell LM, Spencer SA, Carroll WR, Harada S, Yang ES. First-line treatment of widely metastatic BRAF
-mutated salivary duct carcinoma with combined BRAF and MEK inhibition. J Natl Compr Canc Netw 2018;16:1166-70.
Pandey A, Kumar M, Shahi H, Kumari A, Singh S. Novel therapeutic options for recurrent metastatic salivary gland tumors: Review of ongoing clinical trials. Cancer Res Stat Treat 2018;1:10-8. [Full text]
Byrd S, Morris LG. Neck dissection for salivary gland malignancies. Oper Tech Otolayngol Head Neck Surg 2018;29:157-61.
Sciarra A, Gentilucci A, Silvestri I, Salciccia S, Cattarino S, Scarpa S, et al
. Androgen receptor variant 7 (AR-V7) in sequencing therapeutic agents for castratrion resistant prostate cancer: A critical review. Medicine (Baltimore) 2019;98:e15608.
Gargano SM, Senarathne W, Feldman R, Florento E, Stafford P, Swensen J, et al
. Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling. Cancer Med 2019;8:7322-9.
Han J, Liu Y, Yang S, Wu X, Li H, Wang Q. MEK inhibitors for the treatment of non-small cell lung cancer. J Hematol Oncol 2021;14:1.
Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al
. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med 2019;381:1632-43.