An ambitious study of patients from around the world with a rare cervical cancer, neuroendocrine tumors of the cervix (NETc), set out to uncover potential treatments by understanding the molecular basis of the aggressive disease. Since the average survival for patients diagnosed with the rare cervical tumor is less than two years, effective treatments are needed.

Yale Cancer Center (YCC) researchers at Yale School of Medicine (YSM) analyzed the genetic landscape of 66 tumors, the largest series of cervical NET ever reported in scientific literature. They used cutting-edge techniques (whole-exome and RNA-Seq analysis) to sequence all the genes from the tumors and identified the mutations that are crucial for these tumors to grow and endure cancer treatment.

The study, conducted through international collaboration with research groups in Italy, Norway, South Korea, and the United States, revealed atypical genes and pathways that indicate patients with the rare form of cervical cancer could benefit from precision medicine. Researchers say the findings better define the genetic landscape of the rare cervica and suggest that a large subset of these highly aggressive malignancies might respond to existing targeted therapies.

The study was published April 15 in Proceedings of the National Academy of Sciences.

“Our findings have important implications for the development of novel therapies since NETc are currently treated with chemotherapy regimens used for patients with lung cancer,” said senior author Alessandro Santin, MD, co-chief of the division of gynecologic oncology at YCC and a professor of obstetrics, gynecology & reproductive sciences at YSM. “Our genetic data suggest that regimens used for the most common types of cervical cancer in combination with immunotherapies may represent a better choice.”

Stefania Bellone, PhD, first author of the study and associate research scientist in the Department of Obstetrics, Gynecology & Reproductive Sciences at YSM, said that the genetic sequencing of tumors with both adenocarcinoma and neuroendocrine elements found for the first time that the neuroendocrine part of the tumor comes from the same type of cell that leads to the adenocarcinoma, meaning they each have similar genetic mutations typical of epithelial cancer.

The study team sequenced tumor genes from 64 patients affected with the rare form of cervical cancer including two patients with NETc tumors mixed with adenocarcinoma cells, cancer cells that form in glands that line certain organs. Using two fully sequenced patient-derived xenografts (PDX) — in which patients’ cancer cells were implanted in mice — the researchers identified mutations that were crucial for the tumors to grow and survive treatment. The team also studied genes that were not mutated but were amplified in the tumors to give them a growth advantage over normal tissues.

The findings showed many genes had repeated mutations and some had higher levels of certain genetic changes than others. Tumors with a higher number of mutations are potentially more sensitive to immunotherapy.

Corresponding author Joseph Schlessinger, PhD, the William H. Prusoff Professor of Pharmacology at YSM, said that creating two PDX models, each with their own mutation profile, allowed testing of each to determine if they could predict drug responses in living organisms. The approach held promise for tailoring cancer treatments to individual patients.

Other Yale authors on the study include Blair McNamara, Michelle Greenman, Levent Mutlu, Cem Demirkiran, Tobias Max Philipp Hartwich, Yang Yang-Hartwich, Natalia Buza, Pei Hui, Gary Altwerger, Gloria Huang, Vaagn Andikyan, Mitchell Clark, Elena Ratner, Masoud Azodi, Peter E. Schwartz, and Ludmil B. Alexandrov