Immune Modulation May Aid Some Breast Cancer Subtypes


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Sherene Loi, MD, PhD

Carsten Denkert, MD

Sylvia Adams, MD

Lisa M. Coussens, PhD

Tumor-Infiltrating Lymphocytes in Breast Cancer

Jennifer Litton, MD

There may be an immunogenic phenotype in breast cancer that could benefit from immune modulation as part of treatment, according to results from studies that correlated high levels of tumor-infiltrating lymphocytes with both pathologic complete responses and long-term outcomes. Studies presented at the 2013 San Antonio Breast Cancer Symposium lent support to this concept by linking tumor-infiltrating lymphocytes to response to neoadjuvant trastuzumab (Herceptin), response to neoadjuvant carboplatin, and long-term outcomes after adjuvant therapy.

Biomarkers of Response

Sherene Loi, MD, PhD, Head of the Translational Breast Cancer Genomics Lab at the Peter MacCallum Cancer Centre in Melbourne, Australia, reported that for every 10% increase in the levels of tumor-infiltrating lymphocytes, there was a 16% increase (P = .038) in the number of patients achieving a pathologic complete response to neoadjuvant therapy among HER2-positive patients in the GeparQuattro trial.1

Dr. Loi suggested that levels of tumor-infiltrating lymphocytes may serve as biomarkers of response to trastuzumab in primary breast cancer, “something that researchers have been looking for with little success for some time,” she said.

The researchers examined breast cancer tissue from 445 women and identified 156 whose tumors had high levels of tumor-infiltrating lymphocytes. Of those with high levels, 47.4% achieved a pathologic complete response, compared with 31.7% of the entire cohort.

“These data indicate that a patient’s immune system influences outcome and trastuzumab response,” she said. “What we don’t know is why some patients have [tumor-infiltrating lymphocytes] in their breast tumor at diagnosis and others do not. We are actively investigating this.”

Results of genetic profiling in the study suggested that trastuzumab is relieving tumor-mediated immunosuppression. High levels of immune-negative regulators (CTLA-4, PD1) were associated with higher benefit from trastuzumab. In a HER2-driven mammary mouse model, the combination of T-cell checkpoint inhibitors with trastuzumab was synergistic.

The data provide the rationale to evaluate whether the anti–PD-1 agents—currently showing impressive results in melanoma, non–small cell lung cancer, and renal cell carcinoma—when added to trastuzumab can further improve clinical outcomes in HER2-positive disease, she added.

“This study confirms that higher levels of [tumor-infiltrating lymphocytes] are significantly associated with higher clinical benefit from trastuzumab plus chemotherapy, and while further validation is needed, the data suggest that trastuzumab acts not only directly on the tumor but may help antitumor immunity,” Dr. Loi concluded.

Triple-Negative Breast Cancer

In other studies presented in San Antonio, investigators reported that tumor-infiltrating lymphocytes were prognostic and also predictive in women with triple-negative breast cancer.

German investigators reported on a prospective evaluation in 580 patients who had either triple-negative or HER2-positive disease, from the neoadjuvant GeparSixto trial.2 They stratified patients according to the lymphocyte-predominant breast cancer phenotype, which contains more lymphocytes than tumor cells (≥ 60% tumor-infiltrating lymphocytes), finding 20% of HER2-positive tumors to be lymphocyte-predominant breast cancer, and 28% of triple-negative tumors.

Comparing pathologic complete response rates for lymphocyte-predominant vs non–lymphocyte-predominant patients, they found that 60% of patients with lymphocyte-predominant breast cancer (ie, high levels of tumor-infiltrating lymphocytes) achieved a pathologic complete response, compared with 40% of all participants and 34% of non–lymphocyte-predominant breast cancer patients (P < .0005).

“The predictive effect of [tumor-infiltrating lymphocytes] was particularly high in patients treated with carboplatin,” reported Carsten Denkert, MD, Head of the Translational Cancer Research Group at Charité University in Berlin.

For patients with lymphocyte-predominant breast cancer treated with carboplatin plus paclitaxel/doxorubicin, the pathologic complete response rate reached 74% for lymphocyte-predominant, triple-negative breast cancer patients and 78% for HER2-positive patients.

“In [lymphocyte-predominant breast cancer], an increased pathologic complete response rate with carboplatin was observed not only in triple-negative breast cancer but also in HER2-positive breast cancer,” Dr. Denkert said. “Tumor-infiltrating lymphocytes are predictive for response to neoadjuvant chemotherapy, and the prediction is especially good with carboplatin treatment.”

Similar results came from an analysis of 481 participants in Eastern Cooperative Oncology Group (ECOG) 2197 and ECOG 1199, two randomized trials of adjuvant chemotherapy in breast cancer.3 Sylvia Adams, MD, Associate Professor of Medicine at New York University, and colleagues identified stromal tumor-infiltrating lymphocytes in 80% of tumors, which were all triple-negative.

In this group, at least 10% of all cells in the stroma were tumor-infiltrating lymphocytes, and for each 10% increment in stromal tumor-infiltrating lymphocytes at diagnosis there was an 18% reduction in the risk of distant recurrence (P = .04) and a 19% reduction in mortality (P = .01), at a median follow-up of 10.6 years.

In the multivariate analysis, a 10% increase in tumor-infiltrating lymphocytes remained a highly significant independent predictor of disease-free survival (P = .005), distant recurrence–free survival (P = .01), and overall survival (P = .003). As a binary variable, the hazard ratios for disease-free survival were 0.62 when stromal tumor-infiltrating lymphocytes were present (P = .007) and 0.76 when intraepithelial tumor-infiltrating lymphocytes were present (P = .07).

The results in patients with triple-negative breast cancer validate previous findings by Loi et al in 256 patients with triple-negative disease in the BIG 02-98 study,3 which showed that every 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (P = .10 and P = .025), respectively, and 27% and 17% reduced risk of death (P = .035 and P = .023), respectively.

Dr. Adams said this study provides a prospective validation study to BIG 02-98, and thus culminates in level 1 evidence for tumor-infiltrating lymphocytes as a prognostic factor for triple-negative breast cancer.

Looking Ahead

Lisa M. Coussens, PhD, Professor, Chair, and Associate Director of Basic Research at the Knight Cancer Institute of Oregon Health and Science University, Portland, emphasized the finding by Dr. Loi and colleagues that high levels of CTLA-4 and PD-1 correlated with a survival benefit after trastuzumab treatment in a mouse model. “This suggests that immune checkpoint inhibition is a plausible approach to take, in what has been considered a nonimmunogenic type of cancer,” she said, adding that “cytotoxic and targeted therapy alone won’t get us where we need to go.”

She added, “Fortunately, there are many of these inhibitors as well as antibodies to PD-1 and PD-L1 in the pipeline.”

Jennifer Litton, MD, Associate Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, moderated a press briefing where Dr. Loi’s study was presented and commented that the findings could impact how breast cancer is treated.

The prognostic value of tumor-infiltrating lymphocytes, she said, could possibly “change the paradigm of breast cancer treatment.” Research is also needed to determine “how to bring [tumor-infiltrating lymphocytes] into tumors where they are not currently expressed,” she added. ■

Disclosure: Drs. Loi, Adams, Coussens, and Litton reported no potential conflicts of interest. Dr. Denkert is cofounder of Sividon Diagnostics. and his research was funded by the European FP7 Project Responsify.

References

1. Loi S, Michiels S, Salgado R, et al: Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 11, 2013.

2. Denkert C, Loibl S, Salat C, et al: Increased tumor-associated lymphocytes predicts benefit from addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer in the GeparSixto trial (GBG 66/AGO-B). 2013 San Antonio Breast Cancer Symposium. Abstract S1-06. Presented December 11, 2013.

3. Loi S, Sirtaine N, Piette F, et al: Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860-867, 2013.



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