CHECKPOINT INHIBITORS IN TRIPLE NEGATIVE BREAST CANCER
Triple negative breast cancers (TNBCs) account for approximately 20% of all breast cancers. Currently, TNBC, unlike many other breast cancers, lack targeted therapies. Breast cancers are generally considered to be less immunogenic than many other cancers. However, the discovery of Her2 and tumor infiltrating lymphocytes (TIL) provide evidence that this concept is not entirely true. In fact, triple negative breast cancers have a known association with TILs. TILs are known to be an independent prognostic marker of improved survival in early stage triple negative breast cancers. In studies with almost 1000 patients, it was noted that for each 10% increase in TILs, there was a 14% improvement in the relative risk in disease free survival and a 17% reduction in deaths. Furthermore, though lymphocytic infiltrates are seen across all breast cancers, it is seen more frequently in TNBCs.
Evading the immune system is a hallmark for the development and progression of cancer (Hanahan et al. Cell 2011;144: 646-7). T cells are continuously patrolling the body for signs of disease. If a T cell encounters another cell it probes certain proteins on its surface such as PD-1. If the T cell finds that the cell is normal, it leaves the cell alone. If the cell is abnormal or cancerous, an immune attack ensues. In the 1990s scientists discovered that many human cancer cells carry proteins on their surface that enable them to escape attack from the immune system. In fact, many of the cancer cells carry the same protein, PD-L1. When T cells latch on their PD-1 protein onto a cancer cell’s PD-L1 protein, they are fooled into thinking that these are normal cells. Proteins such as PD-L1 are found throughout the body, exemplifying the body’s attempt to protect itself from an aggressive immune attack. These protective proteins such as
Several drugs blocking this immune checkpoint have been developed or are in the development stage. These checkpoint inhibitors block immune checkpoint cancer cell proteins allowing T cells to recognize the invader and lead an immune response. As previously intimated, TNBCs are the most immunogenic of all breast cancers. Consequently, most of the trials have been directed towards these cancers (checkpoint inhibitors).
Monotherapy studies have been carried out with checkpoint inhibitors (CPI) in TNBC with metastatic disease. Only a small number of patients benefited. Higher response rates were noted in small trials using both chemotherapy and CPIs, particularly when using carboplatin in addition to standard chemotherapy. Many trials are now ongoing including 3 phase III adjuvant trials in TNBCs.
In general, responses to CPIs in breast cancer have been modest particularly when compared to more immunogenic tumors such as melanoma and renal cell carcinoma. Biomarkers which select tumors with high PD-L1 expression, as well as other markers, would enrich responses. Novel combination immunotherapies are being intensely studied with ICBs with chemotherapy, targeted therapies, and other immune therapies as well as radiotherapy in the metastatic, neoadjuvant and adjuvant settings.