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

Abstract

Recently, 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.

Keywords: Early-stage triple-negative breast cancer; Immune checkpoint inhibitors; Neoadjuvant therapy; PD-1; Tumour-infiltrating lymphocytes.

Fig. 1

Proposed future strategies for tailoring ICI in early-stage TNBC. De-intensification of the cytotoxic chemotherapy backbone may be feasible for patients with high levels of pre-existing immune activation combined with lower clinical risk. Currently high level of tumour-infiltrating lymphocytes (TIL) and PD-L1 are markers of immune activation. Selection of patients for de-intensification could be improved with ongoing refinement of other biomarkers including tumour mutational burden (TMB), homologous recombination deficiency (HRD) such as BRCA1/2 mutations, and use of immune gene signatures or scores. For patients with HRD, PARP inhibitor could also be incorporated to neoadjuvant immune checkpoint inhibition. Patients whose tumours lack these features have genomic features associated with immune resistance, such as B2M loss and JAK1/2 mutations, and those with high clinical risk should receive the current standard chemotherapy with ICI. The post-surgical phase provides the opportunity to escalate treatment with non-cross-resistant therapies designed to overcome resistance in patients with sub-optimal response. MSI, microsatellite instability; dMMR, mismatch repair deficiency; PD-L1, programmed death ligand-1; BRCA 1/2 mut, germline mutations in BRCA 1/2; TME, tumour microenvironment.