Making Headway in Treatment for Esophageal Cancer
Esophageal cancer is a highly aggressive malignancy affecting nearly 570,000 people worldwide each year. According to the American Cancer Society, nearly 20,000 new esophageal cancer cases will be diagnosed in the United States in 2021. Teams of clinicians and scientists under the leadership of Anil K. Rustgi, MD, at NewYork-Presbyterian/
Identifying a Potential Therapeutic Target for Metastatic Esophageal Cancer
Esophageal squamous cell carcinoma, the most common subtype of esophageal cancer worldwide, typically has a poor prognosis and is often not detected until its late stages when the cancer has metastasized, frequently into the lungs. Columbia researchers have now uncovered a new potential therapeutic target for lung metastasis. The study, which was published in the April 1, 2021, issue of Genes and Development, identifies the role of the BIRC-5 gene and Survivin, the anti-apotic protein it encodes, in metastasis of esophageal squamous cell carcinoma and potentially its role in Survivin-dependent GI cancers.
Led by investigators at Columbia’s NCI-designated Herbert Irving Comprehensive Cancer Center, the research focused on the role of mutant p53 in driving lung metastasis. Using mouse models, the team found that BIRC-5 is highly enriched in mutant p53 cells and identified a pathway through which metastasis of esophageal squamous cell carcinoma is regulated by mutant p53, which is the most common genetic alteration in this disease. P53 is also the most frequently mutated gene across all cancers, giving the researchers’ findings a potential broad application in a number of different cancers.
Further tests showed that mutant p53 binds to Yes-associated protein (YAP), a transcriptional regulator, increasing binding to the BIRC-5 promoter and turning on the expression of Survivin, a key regulator of mitosis and programmed cell death, which allows cancer cells to proliferate. Additionally, they showed that Survivin is upregulated not only in metastatic esophageal squamous cell carcinoma, but also in metastatic pancreatic and colon cancer. This is the first study to provide evidence of the role of Survivin in tumor metastasis and to identify mutant p53 as a key component in regulating Survivin expression.
This is the first study to provide evidence of the role of Survivin in tumor metastasis and to identify mutant p53 as a key component in regulating Survivin expression.
“These findings are exciting because current therapies for esophageal squamous cell carcinoma – chemotherapy, radiotherapy, surgery – may not be as effective in metastatic lesions,” says Qiaosi Tang, PhD, a research fellow in the Rustgi Lab and lead author on the paper. “Targeting Survivin could be an effective therapy for both primary and metastatic esophageal squamous cell carcinoma, as well as other cancers like pancreatic adenocarcinoma and colorectal cancer.”
“While treatment options for metastatic esophageal squamous cell carcinoma have not significantly progressed in the past 20 years, advances in immunotherapy are promising,” says Anil K. Rustgi, MD, Director of the Herbert Irving Comprehensive Cancer Center and senior author on the paper. “Our study provides insights into new potential therapeutic targets that could hopefully build on those promising advances.”
The Columbia team is seeking to advance their findings into a preclinical study, testing the effectiveness of various compounds in modulating Survivin. Currently, there are several Survivin-targeting therapeutic approaches in various stages of development, including RNAi, antisense small nucleotides, small molecular inhibitors, and peptide vaccines. In addition to testing some of these existing compounds, the researchers will look to test a YAP inhibitor, as well as potentially develop a novel compound targeting Survivin.
Under Dr. Rustgi's leadership, Columbia is home to the only NCI Program Project in esophageal cancer. The group also seeks to characterize how squamous cell cancers – esophageal cancer, head/neck cancer, and lung cancer – share common properties, functions, and therapeutic applications.
Mutant p53 regulates Survivin to foster lung metastasis. Tang Q, Efe G, Chiarella AM, Leung J, Chen M, Yamazoe T, Su Z, Pitarresi JR, Li J, Islam M, Karakasheva T, Klein-Szanto AJ, Pan S, Hu J, Natsugoe S, Gu W, Stanger BZ, Wong KK, Diehl JA, Bass AJ, Nakagawa H, Murphy ME, Rustgi AK. Genes and Development. 2021 Apr 1;35(7-8):528-541.
Extending Survival in Esophageal Cancer
Two recent studies have established the role of the immunotherapy drug pembrolizumab (Keytruda) in the treatment of esophageal cancer. The results of two phase 3 clinical trials have demonstrated that pembrolizumab is a safe and effective option when combined with chemotherapy as initial treatment for advanced esophageal carcinoma, both adenocarcinoma and squamous cell carcinoma. The drug was also shown to be effective as a single drug treatment for patients with locally advanced and metastatic squamous cell esophageal cancer who have already received standard chemotherapy. The studies together included over 1,300 individuals with esophageal cancer and over 150 sites around the globe.
Manish A. Shah, MD, Director of the Gastrointestinal Oncology Program, Division of Hematology and Medical Oncology, Chief of the Solid Tumor Oncology Service, and Co-Director of the Center for Advanced Digestive Care at NewYork-Presbyterian/Weill Cornell Medical Center, served as co-author of the study. Dr. Shah is also a member of the Meyer Cancer Center at Weill Cornell Medicine, which, along with NewYork-Presbyterian, served as a lead site for both trials.
In KEYNOTE-590, patients with previously untreated advanced esophageal carcinoma were randomly assigned to receive chemotherapy alone or chemotherapy in combination with pembrolizumab. The primary endpoints of the study were overall survival in esophageal squamous cell carcinoma and in all patients with esophageal carcinoma, as well as in patients with PD-L1 combined positive score > 10. In total, 749 patients were enrolled and randomly assigned to treatment.
Investigators found that patients who received both chemotherapy and pembrolizumab had superior survival, particularly if the PD-L1 combined positive score was > 10. In this population, patients who received the combined therapy of chemotherapy and pembrolizumab had a median survival of 13.5 months compared with 9.4 months with chemotherapy alone. Additionally, the treatment was well tolerated, with no significant difference in treatment related adverse events between the groups. This seminal study led to the approval of pembrolizumab in combination with chemotherapy as initial treatment for esophageal carcinoma.
In addition, if patients did not receive immunotherapy as initial treatment, KEYNOTE-181 examined the role of pembrolizumab alone compared with chemotherapy. Patients enrolled in the study had high levels of PD-L1, and therefore could be expected to respond to the drug. They were randomly assigned to receive either pembrolizumab every three weeks for up to two years or further chemotherapy. Primary end points were overall survival in patients with PD-L1 combined positive score ≥ 10 in patients with squamous cell carcinoma and in all patients.
The investigators found that median overall survival was 9.3 months in the pembrolizumab group compared to 6.7 months in the chemotherapy group. The 12-month overall survival rate was 43 percent in patients taking pembrolizumab compared to 20 percent in those receiving chemotherapy, a two-fold increase. Treatment-related adverse events occurred in 18.2 percent of the pembrolizumab group versus 40.9 percent of the chemotherapy group.
The study’s findings, which were published in the October 6, 2020, issue of the Journal of Clinical Oncology, contributed to the FDA’s approval of pembrolizumab as a second-line treatment for patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma.
Together, these studies led to the FDA’s approval of pembrolizumab in combination with chemotherapy as initial treatment of esophageal carcinoma, both squamous cell and adenocarcinoma, and as a second-line treatment for patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma.
The study also showed that pembrolizumab particularly benefits patients with squamous cell cancer. Median overall survival in patients with this form of esophageal cancer was 8.2 months with pembrolizumab versus 7.1 months with chemotherapy, while survival in all patients was 7.1 months.
“For a very long time we haven’t made progress in treating esophageal cancer,” says Dr. Shah, who notes the standard treatment for metastatic disease for the last 40 years has been chemotherapy with cisplatin and fluoropyrimidine. “The excitement around this study is that we have another treatment option for these patients who typically have a poor prognosis overall. And because immunotherapy has fewer side effects than chemotherapy, not only did people survive longer, they also survived longer with fewer side effects.”
Dr. Shah and his colleagues at NewYork-Presbyterian/Weill Cornell are currently conducting a study of pembrolizumab plus chemotherapy as a first-line therapy in patients with esophageal cancer. “We hope to use the drug earlier and earlier in the course of therapy,” says Dr. Shah. The study design appeared in the April 2021 issue of Future Oncology.
Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomized, placebo-controlled, phase 3 study. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K, KEYNOTE-590 Investigators. The Lancet. 2021 Aug 28;398(10302):759-71.
Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Journal of Clinical Oncology. 2020 Dec 10;38(35):4138-4148.
KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, Mamon HJ, Moehler M, Fu X, Cho BC, Bordia S, Bhagia P, Shih CS, Desai A, Enzinger P. Future Oncology. 2021 Apr;17(10):1143-1153.