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TILs Associated with Benefit from Chemotherapy but Not Trastuzumab

Carlson, Robert H.

doi: 10.1097/01.COT.0000461152.44372.bf
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SAN ANTONIO—Trastuzumab does not benefit all women with HER-2-positive breast cancer, and new research suggests that the reason may be tied to the immune system.

As reported here at the San Antonio Breast Cancer Symposium by Edith A. Perez, MD, Deputy Director at Large for the Mayo Clinic Cancer Center and Professor at Mayo Clinic College of Medicine, Jacksonville, Florida, in the randomized, Phase III NCCTG (Alliance) N9831 trial, women with HER-2 positive breast cancer who had stromal tumor-infiltrating lymphocytes (S-TILs) present in their tumors benefitted from chemotherapy but not from trastuzumab.

Patients with HER2-positive breast cancer who had high levels of the immune cells in their tumors and were treated with chemotherapy alone had a decreased risk of cancer recurrence, compared with their counterparts who had low levels of tumor-infiltrating immune cells. But there was no association between tumor-infiltrating immune cell levels and recurrence-free survival among women who received chemotherapy and the HER2-targeted therapy trastuzumab.

“Our first main finding was that patients with high levels of tumor-infiltrating immune cells did well with chemotherapy alone,” she said in a news conference before her plenary presentation. “Second, the level of tumor-infiltrating immune cells had no impact on the benefit of adding trastuzumab to chemotherapy.”

EDITH A

EDITH A

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945 Patients

The trial included 945 patients with early-stage HER2-positive breast cancer, 489 treated with chemotherapy (doxorubicin-cyclophosphamide followed by paclitaxel) and 456 treated with the same chemotherapy regimen followed by trastuzumab.

Ten percent of all patients had lymphocyte-predominant breast cancer (LPBC), defined as 60 percent or more presence of S-TILs. Non-LPBC patients had less than 60 percent S-TILs in their tumors. Approximately 60 percent of all patients had less than 20 percent S-TILs.

With a median follow-up of 4.4 years, patients who had LPBC had much better outcomes to chemotherapy compared with patients who did not have LPBC, Perez said.

In the chemotherapy-alone arm, 10-year relapse-free survival was 90.9 percent in LPBC patients, versus 64.3 percent in non-LPBC patients, a statistically significant difference with a hazard ratio of 0.22.

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Surprise Finding

But the researchers were surprised when they analyzed data for patients who received chemotherapy plus trastuzumab, which is considered the standard of care for HER-2 breast cancer. There was no statistical difference in outcomes among patients receiving chemotherapy plus trastuzumab whether they had LPBC tumors (high lymphocytic infiltration) or non-LPBC tumors.

In that chemotherapy-plus-trastuzumab arm, 10-year relapse-free survival was almost identical: 80.0 percent in LPBC patients versus 79.6 percent in non-LPBC patients, with a hazard ratio of 1.13.

“For patients randomized to chemotherapy and trastuzumab, the chance of disease recurrence was the same irrespective of the levels of tumor-infiltrating immune cells,” Perez said.

And looked at another way, in LPBC patients, 10-year relapse-free survival was 90.9 percent if they received chemotherapy alone but 80.0 percent if they had chemotherapy plus trastuzumab.

Perez noted that that this was only a trend and not statistically significant. And in non-LPBC patients, 10-year relapse-free survival was 64.3 percent with chemotherapy alone versus 79.6 percent for chemotherapy plus trastuzumab. That difference was statistically significant.

“The message here is, for the 10 percent of patients whose tumors are very highly infiltrated with lymphocytes, we cannot really prove that there is a benefit to using chemotherapy plus trastuzumab,” she said.

These results are the opposite of data in a report earlier in 2014, from the FinHER trial of 209 patients randomly selected to receive chemotherapy or chemotherapy plus nine weeks of trastuzumab. That study, Perez pointed out, found that patients with higher levels of stromal TILs are associated with increased trastuzumab benefit (Loi et al: Ann Oncol 2014;8:1544-1550).

“We found the opposite,” Perez said.

The Alliance N9831 trial had four times as many patients as FinHER, she noted.

These latest results, she said, suggest that TIL levels may provide a biomarker to identify patients who might do well without trastuzumab.

The study was supported by the Donna Foundation and the Breast Cancer Research Foundation.

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Jennifer Litton: Don't Give Up Trastuzumab Yet

The moderator of the news conference, Jennifer Litton, MD, Associate Professor in the Department of Breast Medical Oncology and Director of the Breast Medical Oncology Education Program at the University of Texas MD Anderson Cancer Center, said the study confirms that the small proportion of women who have a high immune filtrate in their tumor just do better with their therapy—“but it also shows this is only in a small proportion of women, 10 percent in this study, so future directions might be to enhance the immune filtrate.”

Litton asked Perez if the study supports not giving trastuzumab to patients with high TIL. Perez replied that it is too early to say that and that the numbers were not statistically significant, but that the trend does give her the impetus to do further research: “Additional large clinical trials are needed before anyone should consider changing clinical practice or omitting HER2-targeted therapy from the treatment regimens for patients who have high levels of tumor-infiltrating immune cells.”

Perez was also asked how TILs might be used therapeutically, so that lymphocytes that are active against cancer go into the tumor.

“Now that we are finding that the presence of lymphocytes at the time we start therapy may have an impact on those therapies, it will be fascinating to see if we can change the milieu of the tumor to see if we can ultimately modify sensitivity to treatments,” she replied.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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