The addition of trastuzumab (Herceptin) to adjuvant chemotherapy undoubtedly transformed HER2-positive breast cancer from one of the most deadly subtypes to a highly treatable disease. Randomized phase III trials established adjuvant trastuzumab as standard of care in HER2-positive breast cancer.1,2 Despite the resounding success of targeting HER2 in breast cancer, a small fraction of patients still suffer from tumor recurrence. Thus, it is critical to better understand the biology driving resistance and develop predictive biomarkers to identify patients unlikely to respond to HER2-targeted therapy.
In their recently reported study, reviewed in this issue of The ASCO Post, Perez and colleagues identified a subset of immune genes that are linked with improved relapse-free survival for patients treated with trastuzumab.3 The data presented in this study have several important translational implications as well as some important limitations.
Mechanism of Action and Tumor Immunity
Extensive preclinical and clinical research has been aimed at defining the precise mechanism of action of trastuzumab. Early in clinical development, it was thought that inhibition of HER2 signaling and downregulation of the receptor was the primary driver of clinical activity. However, subsequent evidence suggests that efficacy also critically depends on activation of immune-mediated tumor destruction.4 Both innate and adaptive immune pathways have emerged as potential mechanisms of action.
The findings in this study build on the notion that trastuzumab efficacy depends on the presence of a basal immune activity within the tumor. Enrichment in immune function genes may represent a marker of localized immune competency, facilitating antibody-dependent cellular cytotoxicity as well as adaptive immunity with trastuzumab therapy.
Questions About Resistance
In this study, patients without enrichment in immune gene expression appeared to have no benefit from the addition of trastuzumab to chemotherapy, with a hazard ratio for relapse-free survival of 0.98 (95% confidence interval = 0.68–1.41, P = .98). What is responsible for this interpatient heterogeneity? Can we identify molecular pathways that lead to a blunted immune response and target them with other agents? Can immune checkpoint inhibitors overcome this resistance?
These are questions that cannot be answered without a deeper biologic understanding of the subset of tumors without immune gene enrichment. Correlation of gene-expression patterns with the presence of tumor-associated immune cells may be a critical starting point.
Tumor-Infiltrating Lymphocytes
The findings in this study highlight a growing breadth of evidence that efficacy of cancer therapy is dependent on immune response. Histologically, the presence of tumor-infiltrating lymphocytes has emerged as a prognostic and predictive biomarker across several malignancies.5
At the 2014 San Antonio Breast Cancer Symposium, the authors presented data from the same N9831 study showing that the benefit of trastuzumab appeared isolated to those patients lacking tumor-infiltrating lymphocytes. This again supports the concept of immune activation as an important mode of action of trastuzumab.
Therefore, “rescuing” patients with tumors lacking tumor-infiltrating lymphocytes may account for the majority of trastuzumab’s clinical efficacy. Conversely, the addition of trastuzumab to chemotherapy in patients with lymphocytes already present in their tumors appeared to lack any benefit. More research is needed in this area to realize the promise of precision medicine for HER2-positive breast cancers.
Biomarker Development
These results should catalyze development of robust clinical biomarkers, so patients likely to fail to respond to HER2-targeted therapy can be steered toward innovative clinical trials testing new approaches. However, one must be cautious when interpreting retrospective gene-expression profiling studies due to numerous pitfalls. Some limitations are generalizable to all gene-expression biomarker studies. For instance, tissue heterogeneity of tumor samples leads to difficulty in interpretation and variability of gene expression, since detected transcripts may be arising from numerous cell types (ie, tumor cells, immune cells, vascular endothelial cells).6
Limitations specific to the current study include the observation that immune-enriched tumors were significantly smaller than nonimmune-enriched tumors (P < .0001). This finding is problematic and potentially confounds the results. As with any proposed biomarker, extensive prospective validation would be necessary before its incorporation into clinical practice. In reality, hundreds of publications on predictive and prognostic gene-expression biomarkers have been published, but an exceedingly small number have demonstrated clinical utility.
Future Directions
Using an empirical, unbiased methodology, Perez and colleagues identified a strong association between immune gene expression and the efficacy of adjuvant trastuzumab. As the nuances of breast cancer tumor immunology continue to be dissected, refinement of our treatment algorithms and the addition of novel therapies will undoubtedly improve outcomes. Given the recent success of immune therapies in other tumor types, we envision with great excitement its eventual expansion into breast cancer. ■
Disclosure: Drs. Sweis and Olopade reported no potential conflicts of interest.
References
1. Perez EA, Romond EH, Suman VJ, et al: Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 29:3366-3373, 2011.
2. Perez EA, Suman VJ, Davidson NE, et al: Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 29:4491-4497, 2011.
3. Perez EA, Thompson EA, Ballman KV, et al: Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. J Clin Oncol 33:701-708, 2015.
4. Bianchini G, Gianni L: The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 15:e58-e68, 2014.
5. Gajewski TF, Schreiber H, Fu YX: Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014-1022, 2013.
6. Rodriguez-Gonzalez FG, Mustafa DA, Mostert B, et al: The challenge of gene expression profiling in heterogeneous clinical samples. Methods 59:47-58, 2013.
Dr. Sweis is a hematology/oncology fellow at the University of Chicago. Dr. Olopade is Director of the Center for Clinical Cancer Genetics, University of Chicago Medicine.
