Researchers Checking TILs for Clues Against Breast Cancer


CME NUGGETS

Ed Susman

Mr. Susman is a freelance medical writer based in Florida, USA. He travels worldwide to report from medical conferences, writing regularly for wire services, internet websites, and medical journals such as the Journal of the National Cancer Institute and AIDS.

For comments, edwardsusman@cs.com


VIENNA, Austria – Stromal tumor infiltrating lymphocytes (TIL) that can be detected in breast cancer may be a ticket to controlling the disease, researchers suggested here at the 16th St. Gallen Breast Cancer Conference.

Patients with triple negative breast cancer – a notoriously difficult to treat form of metastatic breast cancer – appear to gain a survival advantage if their tumors contain higher levels of TILs compared with patients who do not have higher TIL counts, said Shereen Loi, MD, PhD, head ofthe Translational Breast Cancer Genomics and Therapeutics Lab at the Peter McCallum Cancer Centre, and associate professor of medicine at the University of Melbourne in Australia.

“There is strong rationale to target immune pathways in breast cancer,” she said in her oral presentation. “There is strong (Level 1B) evidence that TILs biomarker significantly improves prognostic estimates of early stage triple negative breast cancer.”

Although pathologists have observed TILs in breast cancer for more than 100 years, Dr. Loi suggested that an appreciation of their role in modulating breast cancer is now just being understood. “In some patients it is a very dense infiltration and some patients have hardly any infiltration,” she said. “This begs the question that many labs, including mine, have been asking: why some breast cancers have these immune infiltrates and what is the clinical relevance. “It wasn’t until the advent of genome wide technologies that we began to realize that breast cancer was not just one disease but there were at least three different subtypes and the immune signal in breast cancer became clearer in that it seemed to be most prognostic in the triple negative and HER2-positive breast cancer subtypes,” she said.

She said that tools are available online that can help everyone determine the level of tumor infiltrating lymphocytes (TILs) in breast cancer tissue. “Breast cancer is not a well infiltrated as other solid tumors such as melanoma and lung cancer, but the development of the training tools allows researchers to access a large number of breast cancer specimens to be able to assess the value of this biomarker in the setting of breast cancer,” Dr. Loi said.

She and colleagues have performed a pooled analysis of more than 2000 patients in 9 studies that found that higher TIL quantity was significantly associated with younger age, smaller tumor size and less nodal involvement. The researchers calculated that for every 10 percent increment of TIL, the risk of relapse or death was reduced 17 percent. “This suggests that anti-tumor activity is controlling tumor size to some extent in some patients. “The information provided by studying TIL levels provide as much prognostic value as gene assays, “she said.

In the pooled analysis, women without nodal disease and with high TIL had excellent distant disease-free survival at three years is 97 percent and overall survival was 99 percent, but even the patients with 1-3 nodal involvement still had very impressive distant disease-free (89 percent) and overall survival (93 percent). Even patients with 4 or more positive nodes did better if they had high TIL, Dr. Loi said.

“So if we can modulate the immunity to increase their TIL counts we can further improve their survival,” she said. “While the tumor biomarker doesn’t directly influence your treatment per se because all the studies were performed within the context of chemotherapy, this does allow patients to have a more accurate understanding of their prognosis and potentially may allow us to design clinical trials in the future to target the higher risk patients.”

This biomarker will be included in the WHO “Classification of Tumors of the Breast” this year, she said.

Surgery first?

In other presentations at the meeting which is conducted every two years, Eric Winer, MD, director of breast oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Faber Cancer Institute/Harvard Medical School, Boston, Massachusetts, in a special lecture, suggested that surgery before or after chemotherapy is patient and tumor dependent.

“At this point there is no survival advantage between adjuvant and neoadjuvant therapy,” said Dr. Winer, “Since studies have shown no survival benefit, it is important to look at when one would perform adjuvant therapy, or surgery first.”

He said that the goals of both adjuvant and neoadjuvant therapy is the same: To eradicate micrometastatic disease and to improve overall survival. “Ultimately, it all comes down to how long and how well you live,” Dr. Winer said in his presentation.

“Neoadjuvant therapy is the same treatment as adjuvant therapy except if it is given before rather than after surgery most of the time,” he said. “But with neoadjuvant therapy we are also trying to decrease the extent of the surgery, provide prognostic information, identify candidates for additional treatment approaches; potentially to test de-escalation trials and strategies and to conduct tissue-intensive trials.”

The adjuvant surgery approach would work for patients who don’t need some type of therapy to reduce the size of the tumor or improve surgical options. “This is true for most early stage cancers – for Stage 1 HER2-positive disease,” Dr. Winer suggested. “We can give a much easier chemotherapy regimen than we would give for patients who have Stage 2 or Stage 3 disease. But we need to know the anatomic extent of the disease.

“The same is true in triple negative disease where many of you would not give an anthracycline and taxane based regimen to a patient who has the smallest of all tumors whether you call that T1a, T1b or all Stage 1,” he said.

Dr. Winer suggested that in Stage 1 or 2 estrogen receptor positive disease that it intermediate in grade additional information may be needed to determine treatment options. “In this situation we often use genomic profiles to try to help make decisions about adjuvant therapy, but particularly when those profiles don’t give us such clear answers; the anatomic extent of disease may influence your decisions in clinical practice.

“When it is difficult to follow what is going on in the breast because the tumor is not palpable or imaging for whatever reason is not clear, it is difficult to get excited about neoadjuvant therapy,” he said. “I will acknowledge that there are going to be situations when you will decide to do surgery first and you will find more disease in the breast or lymph nodes than you initially thought would be there and you may regret it, but this isn’t common and it doesn’t change my approach to what the situation is about.”

Dr. Winer said that neoadjuvant approaches to treatment may depend on the stage and grading of disease. “For many of us, patients who have Stage 2 of Stage 3 triple negative breast cancer or HER2-positive disease are probably optimally treated with the neoadjuvant approach,” he said. “If it is clear that a women is going to have to get chemotherapy, she might as well get that therapy upfront. If optimal surgical therapy will be facilitated by neoadjuvant treatment then that is the approach you want to take whatever that neoadjuvant therapy is.”

However, he did provide a caution for using the neoadjuvant route. “There is one twist,” he said. “That is, to be successful giving neoadjuvant therapy, you really need to have a multidisciplinary team in place that is adequately functioning because surgeons and medical oncologists and radiation oncologists need to be able to talk to one another and communicate about the patient.”

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