Breast Cancer With High TIL Levels: Skip the Trastuzumab?

Zosia Chustecka

December 10, 2014

Intriguing new findings from a study of stromal tumor infiltrating lymphocytes (Str-TILs) in breast cancer patients with HER2 tumors suggest that there is a small subgroup of patients (about 10%) who may not benefit from the addition of trastuzumab (Herceptin, Genentech, Inc) to chemotherapy.

The study was presented here at San Antonio Breast Cancer Symposium (SABCS) 2014 by Edith A. Perez, MD, deputy director at large for the Mayo Clinic Cancer Center.

This small proportion of patients who had high levels of Str-TILs in the tumor specimens did well whether they were treated with chemotherapy alone or with chemotherapy plus trastuzumab, suggesting that these patients may not need trastuzumab, sparing them side effects and reducing costs.

However, this research is too early yet to influence clinical decisions, especially a decision to withhold a drug such as trastuzumab, which has been shown over and over again to save lives, commented Jennifer Litton, MD, from the MD Anderson Cancer Center, in Houston, Texas. She was not involved in the study, and moderated a press briefing at which it was highlighted.

This is hypothesis-generating, Dr Litton emphasized. Before making a decision to withhold a therapy, we would need data from randomized clinical trials, she said. Maybe in the future, we can give less therapy to this small subgroup of patients who have a high levels of Str-TILs, she told Medscape Medical News.

But she emphasized that this study shows that for the vast majority of breast cancer patients with low levels or no Str-TILs in the tumor tissue, the addition of trastuzumab makes a big difference, she said. "This was really striking," Dr Lifton commented. "These patients really needed the trastumzumab," she said.

She suggested that it was the results in this patient subgroup (those who did not have STr-TIL, and who represented 90% of the total population) that drove the positive results for the total study population, which were reported previously.

Analysis of Str-TILs in Tumor Tissue

The new results come from an analysis of data from 945 patients with HER2 breast cancer who participated in the N9831 study, which investigated the addition of trastuzumab to adjuvant chemotherapy (doxorubicin plus cyclophosphamide, followed by paclitaxel). The median follow-up was 6.9 years.

"We have previously reported that adding trastuzumab to chemotherapy significantly improved recurrence-free and overall survival in N9831," lead author Dr Perez said in a statement. "However, not all patients benefited from addition of trastuzumab, and some did well with chemotherapy alone."

For the new study, tumor tissue was analyzed for Str-TILs, and specimens found to have high levels (defined as ≥60% of cells in the sample section being immune cells) were classified as "lymphocyte predominant breast cancer (LPBC)." This was found in 10% of samples.

This subgroup of LPBC patients (who had high levels of STr-TILS) did well with chemotherapy alone. In fact, the relapse-free survival rate (RFS) was slightly worse with the addition of trastuzumab, although the difference was not statistically significant. In this subgroup, the estimated 10-year RFS was 90.9% with chemotherapy alone vs 80% with chemotherapy plus trastuzumab (P = 0.22).

In contrast, in the remaining larger subgroup of patients without high levels of Sr-TILs, there was a statistically significant difference in the outcome: the 10-year RFS was 64.3% with chemotherapy alone vs 79.6% with chemotherapy plus trastuzumab (P < .0001).

"These results suggest that levels of tumor-infiltrating immune cells may provide a biomarker to identify patients who might do well without trastuzumab, but we must conduct additional large clinical trials before we can consider changing clinical practice and omitting HER2-targeted therapy from the treatment regimens for patients who have high levels of tumor-infiltrating immune cells," Dr Perez stated.

This is a "very provocative" paper, which suggests trastuzumab works by stimulating the immune system, commented Mary Disis, MD, from the University of Washington in Seattle, who was discussant for the paper. She noted that very elegant animal studies have shown that "if you totally abrogate adaptive immunity and T-cell immunity in those models, trastuzumab-like antibodies don't work." This study suggests that if patients are already autoimmunized against the breast cancer and have these high levels of TILs, then the use of trastuzumab does not make a difference, because the drug's main action is to stimulate adaptive immunity, she said.

Dr Disis noted that around 30% of patients in the study were found to have no Str-TILs; for these patients, "we need to think about a new strategy," she said. Another 60% were found to have intermediate levels, and here "we have to think about how to generate more T cells."

And then there is the 10% with high levels of Str-TILs whose adaptive immunity is already maximally stimulated, and for whom trastuzumab adds no extra benefit. "In fact, I want to be provocative and note that the patients with addition of trastuzumab fared a little worse, although the difference was not significant." She suggested that once the immune system is already maximally activated, further activation may be detrimental, and may lead to T-cell exhaustion.

This study was supported by funds from the 26.2 With Donna Foundation and the Breast Cancer Research Foundation. Dr Perez, Dr Litton, and Dr Disis have reported no relevant financial relationships

San Antonio Breast Cancer Symposium (SABCS) 2014. Abstract bS1-06, presented 10 December, 2014.


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