Immunotherapy in Early-Stage Triple-Negative Breast Cancer: Where Are We Now and Where Are We Headed?

Opinion statementRecently, the addition of PD-1 pathway targeting immune checkpoint inhibitors (ICI) to standard neoadjuvant chemotherapy for early-stage triple-negative breast cancer (TNBC) has been shown to improve rates of pathological complete response (pCR), as well as event-free survival regardless of attainment of pCR. Recurrent TNBC remains a devastating diagnosis and thus novel treatments that improve chance of cure in early-stage TNBC should be promptly integrated into standard of care paradigms. However, approximately 50% of patients with early TNBC will experience pCR with chemotherapy alone, and the addition of ICI carries the risk of sometimes permanent immune-related toxicities. This raises the critical question whether all early-stage TNBC patients should receive ICI in combination with neoadjuvant chemotherapy. As yet, there is no predictive biomarker to select patients most likely to benefit from ICI; however, it would seem that at least all node positive patients should receive an ICI with their neoadjuvant chemotherapy, on the basis of high clinical risk and potential to increase their pCR rate and ultimately the chance of cure. It is plausible that some lower-risk (stage I/II) TNBC demonstrating strong pre-existing immune activation (high tumor-infiltrating lymphocytes (TILs) and/or PD-L1 expression) may be successfully treated with ICI in combination with less cytotoxic chemotherapy, and this requires further evaluation in clinical trials. The contribution of the adjuvant phase of ICI on clinical benefit is unclear even in patients who do not achieve a pCR and long-term data from ongoing studies without adjuvant ICI component may help inform us on an appropriate strategy in the short term. Similarly, the potential benefit of other adjuvant therapies in patients with poor response to neoadjuvant ICI with chemotherapy, including capecitabine and olaparib with or without ICI, is also unknown, but is rational on the basis of administering a non-cross-resistant anti-tumour agent. In conclusion, the addition of neoadjuvant ICI to chemotherapy significantly improves both the quality and quantity of the anti-tumour T cell response, suggesting that improvements in recurrence-free survival occur through better immune protection from cancer. In the future, development of ICI agents that target tumour-specific T cells may favourably alter the toxicity profile, improving the risk-benefit ratio for survivors.

Automated summary

Recently, adding PD-1 pathway targeting immune checkpoint inhibitors (ICI) to neoadjuvant chemotherapy has been shown to improve outcomes for early-stage triple-negative breast cancer (TNBC) patients. However, the use of ICI carries the risk of immune-related toxicities and there is currently no predictive biomarker to select patients who will benefit the most. It is suggested that all node positive patients should receive ICI, while lower-risk TNBC patients with strong pre-existing immune activation may benefit from ICI combined with less cytotoxic chemotherapy. The impact of adjuvant ICI and other therapies in non-responders requires further investigation.