Composite Biomarker Needed to Predict Benefit of Immunotherapy in Triple-Negative Breast Cancer
Although there is a biomarker that predicts response to the one approved immunotherapy agent for metastatic triple-negative breast cancer, “it is important to note there are no biomarkers of response to neoadjuvant immunotherapy in early-stage triple-negative breast cancer,” Elizabeth A. Mittendorf, MD, PhD, stated at the 2021 Lynn Sage Breast Cancer Symposium.1
Several potential biomarkers studied, including PD-L1 status, tumor-infiltrating lymphocytes, and high tumor mutational burden, have predicted overall response to treatment, but not specifically to immunotherapy. “I personally anticipate that we are going to need a composite biomarker to predict benefit of immunotherapy,” Dr. Mittendorf said. That composite could contain “tumor markers, immune aspects of the microenvironment, and host factors including the patient’s peripheral immunity and gut microbiome,” she added. “Given the toxicities associated with immunotherapy, clinicians are incentivized to identify a biomarker of response.”
Elizabeth A. Mittendorf, MD, PhD
Dr. Mittendorf is Director of the Breast Immuno-Oncology Program, Dana-Farber Cancer Institute, Boston, and Professor of Surgery, Harvard Medical School. The symposium was sponsored by Northwestern Medicine/Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
“Pembrolizumab is now the only approved immunotherapy agent for PD-L1–positive metastatic triple-negative breast cancer. We favor assessing PD-L1 status using the 22-C3 assay,” Dr. Mittendorf said. “The best site to test remains unclear.”
“Positivity rates vary greatly for different metastatic sites,” Dr. Mittendorf explained, with consistently low rates of positivity in the liver and high rates of positivity in lymph nodes, which “may reflect the large number of immune cells in the lymph nodes.” Differences between primary and metastatic tumors, as well as among different metastatic sites, “likely reflect true immunologic differences between the sites,” she noted. “We do not yet have enough clinical experience to correlate organ site–specific responses.”
Checkpoint Blockade Monotherapy
The KEYNOTE-119 study2 provides “some insight” into whether PD-L1 expression can predict response to checkpoint blockade monotherapy, Dr. Mittendorf noted. Patients with one or two prior systemic treatments for recurrent metastatic triple-negative breast cancer were randomly assigned to pembrolizumab or investigator’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine. Randomization was stratified by high vs low PD-L1 tumor status and by a history of neoadjuvant or adjuvant therapy vs no prior therapy.
Although pembrolizumab did not significantly improve overall survival compared with chemotherapy, for patients whose tumors had the highest levels of PD-L1 expression, “you begin to see a separation of the curves, suggesting that for many of the highest expressing PD-L1 tumors, pembrolizumab monotherapy may be effective,” Dr. Mittendorf said. However, these data, she added, “require prospective validation.”
Neoadjuvant Immunotherapy Trials
In several neoadjuvant immunotherapy trials, tumor-infiltrating lymphocytes, PD-L1, tumor mutational burden, and gene expression “did predict response to neoadjuvant therapy, but not specifically to the addition of PD-1/PD-L1 inhibitor,” Dr. Mittendorf stated.
MHC-II, “previously identified as a biomarker predicting response to immunotherapy in melanoma,” is now being investigated in several cohorts of patients with breast cancer, Dr. Mittendorf noted. A review of the I-SPY2 trial offered the “opportunity to look at a study that had randomly assigned patients to either chemotherapy alone or chemotherapy plus pembrolizumab.” The investigators found that “expression of MHC-II did predict benefit to immunotherapy,3” Dr. Mittendorf noted. “However, it did not predict benefit to chemotherapy, suggesting it could a biomarker that differentiates. Validation is required in larger studies.”
Tumor-infiltrating lymphocytes have not been shown to be predictive of response to immunotherapy. “It has been well studied and published that tumor-infiltrating lymphocytes are both prognostic and predictive in breast cancer,” Dr. Mittendorf stated.
Tumor-infiltrating lymphocytes can be stromal or intratumoral, she explained, although “stromal is certainly more common.” Tumor-infiltrating lymphocytes are “primarily T cells; as the number of tumor-infiltrating lymphocytes increases, so does the proportion of CD8-positive T cells, which are cytotoxic T cells.”
Early data4 found that patients with triple-negative breast cancer who had greater than 50% lymphocytic infiltrates “had an improved disease-free survival compared with patients whose tumors were not lymphocyte-predominant,” Dr. Mittendorf reported. “A number of studies have shown that the presence of tumor-infiltrating lymphocytes is predictive of response to neoadjuvant chemotherapy.”
Even Without Chemotherapy
“A very interesting study” from the Netherlands, Dr. Mittendorf noted, assessed the prognostic value of tumor-infiltrating lymphocytes in young patients with triple-negative breast cancer who had N0 disease and therefore did not receive chemotherapy. “For patients who had a very high level of stromal tumor-infiltrating lymphocytes, at least 75%, the 10-year overall survival rate was 95%,5” Dr. Mittendorf reported.
A subsequent analysis restricted to patients with T1N0 disease found that for patients with a high level of stromal tumor-infiltrating lymphocytes, at least 75%, “at 10 years, the rate of distant metastases was 3%, much less than the 16.7% of a second primary in that population of patients,” she said.
Dr. Mittendorf continued: “These data are consistent with data published by Park in 2019,6 who looked at the prognostic value of tumor-infiltrating lymphocytes in patients with stage I triple-negative breast cancer who had not received chemotherapy.” In that study, patients with tumor-infiltrating lymphocytes levels of at least 30% had improvement in distant disease–free and overall survival, compared with patients who stromal tumor-infiltrating lymphocytes levels of less than 30%. For patients with levels of tumor-infiltrating lymphocytes greater than 30%, “outcomes were equally excellent when compared with patients who did receive chemotherapy,” she added.
“I think it may be possible to identify a high tumor-infiltrating lymphocyte, low-risk triple-negative breast cancer population,” Dr. Mittendorf concluded. “We know that tumor-infiltrating lymphocytes are associated with a better prognosis after adjuvant chemotherapy. We also know there are higher pathologic complete response rates with neoadjuvant chemotherapy for those whose tumors express a large number of tumor-infiltrating lymphocytes, and there are good outcomes in the absence of chemotherapy for select patients. Studies are now in development using tumor-infiltrating lymphocytes to select patients with a favorable prognosis who may be appropriate for de-escalated therapy.”
DISCLOSURE: Dr. Mittendorf has received honoraria from Physician Education Resource; has served as a consultant or advisor to Genomic Health, Genentech/Roche, Merck, Peregrine Pharmaceuticals, Sellas Life Sciences, and TapImmune Inc; and has received institutional research funding from AstraZeneca, EMD Serono, Galena Biopharma, Genentech/Roche, and GlaxoSmithKline.
1. Mittendorf E: Immune biomarkers. 2021 Lynn Sage Breast Cancer Symposium. Presented October 1, 2021.
2. Winer EP, Lipatov O, Im SA, et al: Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): A randomised, open-label, phase 3 trial. Lancet Oncol 22:499-511, 2021.
3. Gonzalez-Ericsson PI, Wulfkhule JD, Gallagher RI, et al: Tumor-specific major histocompatibility-II expression predicts benefit to anti-PD-1/L1 therapy in patients with HER2-negative primary breast cancer. Clin Cancer Res. July 27, 2021 (early release online).
4. 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.
5. De Jong VMT, Wang Y, Opdam M, et al: Prognostic value of tumor infiltrating lymphocytes in young triple negative breast cancer patients who did not receive adjuvant systemic treatment; by the PARADIGM study group. ESMO Virtual Congress 2020. Abstract 159O. Presented September 20, 2020.
6. Park JH, Jonas SF, Bataillon G, et al: Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers who did not receive adjuvant chemotherapy. Ann Oncol 30:1941-1949, 2019.