What These Results Mean

“From these observations, we conclude that metastatic breast cancers are more immune-depleted and immune-inert compared with primary tumors,” Dr Pusztai said. “We are not surprised by this; in fact, we predicted it based on our earlier observations made from the TCGA [The Cancer Genome Atlas] data,” he added.5,6 He indicated that these observations support the hypothesis that the process of metastasis requires immune evasion in the primary tumor site.

Dr Pusztai indicated that since clinically detectable metastatic lesions are more immune inert and express lower levels of many immuno-oncology targets, such as PD-L1, it is likely that anti-PDL1/PD-L1 therapy will be less effective than the same therapy against disease in primary tumors of the breast.

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However, he emphasized that the lower level of immune activation does not imply there would be a complete absence of a response to immune therapies. “Indeed, clinical trials have demonstrated clinical activity of PD-1/PD-L1–targeted agents in metastatic breast cancer, but the single-agent response rates were low, in the range of 5% to 18%,” he said. “Immune therapy might work better in the early stages of the disease and in clinically undetectable micrometastatic lesions. This is now being tested in several ongoing neoadjuvant and adjuvant trials,” he added.

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“Our study, and any similar study, can only examine macrometastasic lesions, and we can only speculate about the immune status of micrometastasis that is the target of systemic adjuvant therapies.” Dr Pusztai noted. He also pointed out that several adjuvant trials are currently open that are testing PD-1/PD-L1–targeted therapies in stage II to stage III breast cancers.

“We have identified immune cell gene expression differences between primary tumors and metastases that suggest mechanisms that explain the immune-depleted status of metastatic lesions,” Dr Pusztai explained. “We hypothesize that manipulating these molecules could increase the immunogenicity of the cells found at metastatic sites in breast cancers,” he said. “We also describe several immunosuppressive mechanisms that we detected in metastasis, and blocking these could also possibly improve immunotherapy efficacy,” he added.

Dr Pusztai indicated that the same phenomenon may likely occur in other cancers — that is, metastatic lesions becoming less immunogenic or more immunologically inert compared with the tissue extracted from the primary tumor. “This would predict that more patients will respond to immunotherapies at earlier stages of their disease, rather than at late stages,” he concluded.


  1. Szekely B, Bossuyt V, Li X, et al. Immunological differences between primary and metastatic breast cancer [published September 10, 2018]. Ann Oncol. doi: 10.1093/annonc/mdy399
  2. Cimino-Mathews A, Ye X, Meeker A, Argani P, Emens LA. Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Hum Pathol. 2013; 44(10):2055-2063.
  3. Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol. 2016;47(1):52-63.
  4. Ogiya R, Niikura N, Kumaki N et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Sci. 2016;107(12):1730-1735.
  5. Karn T, Jiang T, Hatzis C, et al. Association between genomic metrics and immune infiltration in triple-negative breast cancer. JAMA Oncol. 2017;3(12):1707-1711.
  6. Safonov A, Jiang T, Bianchini G, et al. Immune gene expression is associated with genomic aberrations in breast cancer. Cancer Res. 2017;77(12):3317-3324.