Basis for molecular diagnostics and immunotherapy for esophageal cancer

Abstract

Esophageal cancer (EC) is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field's most dire survival statistics. Areas covered: Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for EC. Expert commentary: Of the 12 FDA-approved therapies in EC, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy.

Keywords: CTLA-4 inhibitors; Esophageal cancer; PD-L1 inhibitors; combination immunotherapy; esophageal adenocarcinoma; molecular oncology; precision medicine; proteomics; targeted chemotherapy; targeted therapy.

Figure 1

Five-year survival rates for some of the most common cancers in the United States in 1975 paired with current available figures. [14].

Figure 2

Brief history of precision medicine in medical oncology. A birds-eye-view of how more precise patient management strategies have contributed to improved survival rates in all cancers over the last century [14,82]. EGFR – epidermal growth factor receptor; KRAS - V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; ER – estrogen receptor; HER2 -- Receptor tyrosine-protein kinase erbB-2; PR – progesterone receptor.

Figure 3

Potential pathology-based workflow for esophageal tumor specimen to optimize patient management strategies for esophageal cancer cases in the event the patient’s surgeon and oncologist opt for esophagectomy followed by adjuvant therapy. We recommend this proteomic panel to be utilized in order to scrutinize potential drug targets or chemotherapy resistant markers expressed in a patient’s tumor. ERCC1 – Excision Repair Cross-Complementation Group 1; TUBB3 – Tubulin Beta 3; TOPO2A - Type II Topoisomerase; TOPO-I – Topoisomerase-1; HER2 – Receptor tyrosine-protein kinase erbB-2; EGFR – Epidermal growth factor receptor; PD-L1 - Programmed death-ligand 1; 5-FU -- Fluorouracil. Crossed out drugs names = do not use. Non-crossed out drug names = consider for use.

Figure 4

Utilizing combination immunotherapy could be an aggressive approach enabling improved survival rates in esophageal cancer patients by stimulating the immune system to halt erratic cell proliferation via two mechanisms of action rather than one [51,52]. The frame on the left demonstrates immune system activation via CTLA-4 blockade with drugs like tremelimumab where inhibition of the B7 ligand on the antigen presenting cell (APC) causes T-cells to proliferate and migrate toward the tumor. The center frame shows that once T-cells are signaled to target antigens like a tumor – that blocking PD-L1 (with drugs like MEDI4736) will allow T-cells to engage in a fight with the tumor cells by inhibiting a connection to PD-1 which is expressed on the T-lymphocyte. If PD-L1 is left unadulterated then the T-cell will recognize the tumor as “self” and be diverted from destructing the cancer. The far right frame shows that utilizing both mechanisms of action as a combination therapy has produced more robust tumor regressions in early clinical trials, which gives optimism to medical oncologists. CTLA4 – cytotoxic T-lymphocyte-associated protein 4; PD-L1 – program death-ligand 1.