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Roswell Park-Led Team Creates TILs-Based Scoring Tool That Correlates with Breast Cancer Survival

Score estimates number of intratumoral tumor-infiltrating lymphocytes (TILs) in breast cancer subtypes

A team at Roswell Park Comprehensive Cancer Center has uncovered a link between survival and the number of tumor-infiltrating lymphocytes (TILs) in the tumors of breast cancer patients. Kazuaki Takabe, MD, PhD, FACS, Clinical Chief of Breast Surgery, Breast Program Leader and Breast Disease Site Leader at Roswell Park, served as principal investigator of the new study published in Annals of Surgery. Rongrong Wu, MD, and Masanori Oshi, MD, of the Department of Surgical Oncology at Roswell Park were first authors of the study, which was completed in collaboration with colleagues in Japan.

The study focuses on T lymphocytes — special white blood cells that are part of the immune system and capable of destroying cancer cells. When they work their way close to a tumor, they are called tumor-infiltrating lymphocytes (TILs). Prior research has shown that the number of TILs in the tumor affects breast cancer progression, response to treatment and survival.

However, most previous studies focused on TILs located in the tumor stroma, the tissue that surrounds the bulk tumor and contains non-cancerous cells that do not come in direct contact with cancer cells. Intratumoral TILs, on the other hand, are in direct contact with cancer cells — a fact that could mean they are more significant biologically than stromal TILs. The team hypothesized that the number of intratumoral TILs could be linked to cancer aggressiveness, survival and response to neoadjuvant chemotherapy, which is given prior to surgery.

Despite their potentially key role in outcomes, intratumoral TILs have been the subject of few studies. This is due partly to the fact that there are fewer T lymphocytes inside the tumor than the stroma, and that they move around in living tissue, making it harder to quantify them. To overcome those challenges and learn more about the role of intratumoral TILs, Dr. Takabe’s team joined forces with collaborating investigators from Tokyo Medical University, Yokohama City University Graduate School of Medicine, and Hyogo Medical University.

Using The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium and Gene Set Enrichment Analysis databases, they analyzed data from 5,870 breast cancer patients with various subtypes of breast cancer: triple-negative breast cancer (TNBC), estrogen receptor-positive breast cancer (ER+) and human epidermal growth factor receptor 2-positive or -negative breast cancer (HER2+ and HER2-).

To overcome the difficulties of quantifying the number of intratumoral TILs, the researchers employed a method called computational deconvolution of bulk tumor transcriptomes, which made it possible to estimate the numbers of 19 types of lymphocytes in a tumor based on messenger RNA expression profiles. The team found that the effects of intratumoral TIL volume varied by breast cancer subtype.

“We established a score that estimates the amount of TILs inside a malignant breast tumor,” explains Dr. Takabe. “We found that higher scores on our index are associated with better overall survival in HER2-overexpressing and triple-negative breast cancer.”

In ER+ and HER2- breast cancers, the score was associated with more robust immune responses and cell multiplication.

“We found that our score was associated with complete response — disappearance of cancer — after neoadjuvant chemotherapy in half of the cohorts we analyzed,” adds Dr. Takabe. “Even if the patient did not have immunotherapy, the amount of TILs in the tumor, measured by our score, was associated with patient survival.”

The investigators anticipate that future research on different kinds of TILs in breast cancer subtypes will shed more light on the various roles they play and inform the use of immunotherapy for treating those subtypes.

Results of the study were presented in April at the 143rd annual meeting of the American Surgical Association in Toronto, Ontario, and will be published in print in the October issue of Annals of Surgery.

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