The pathway PD1/PD-L1 is a key player in the mechanism of tumor escape from immune surveillance but, the role of PDL1 as a marker of outcome in breast cancer patients is still unclear to date. We aim to analyze PD-L1 expression on circulating tumor cells during neoadjuvant chemotherapy (NACT) in locally advanced breast cancer patients. In our opinion, CTCs better than other samples can describe molecular portrait of the tumor, being a critical step in the metastatic process and quite often present in the blood in the very early phase of neoplastic disease. Moreover, serial liquid biopsies investigating PD-L1 expression could recreate a dynamic portrait of the cancer complexity able to inform on the genomic heterogeneity during treatment. To date, PD-L1 expression on breast CTCs during NACT has never been investigated. We hope in the future liquid biopsy could guide breast cancer management, as a tool that very early intercept ensuing resistance before clinical tumor progression, allowing prompt treatment modifications. Moreover, PD-L1 positive CTCs could be a very promising biomarker to predict pRC or to early identify patients with poor response to treatment, who need a more aggressive treatment and a closer follow up. Preliminary results show a high expression of PD-L1 positive CTCs in BRCA1/2 mutated breast cancers, regardless of intrinsic subtype, with the highest rate found in basal breast cancers. This observation support the hypothesis that PD1/PDL1 pathway could be the principal mechanism of the immune escape in BRCA1/2 mutated cancer and in all tumors with DNA repair mechanism defects.
We hypothesize that the presence of CTCs with immune evasion skills such as PD-L1 expression could represent a very early signal of immune surveillance defeat and metastatic progression.
Monitoring PD-L1 expression on CTCs as well as expression of molecules involved in immune escape in early disease could mirror the immune status of the tumor and how the disease will evolve in the near future.
In the vast majority of the studies, the expression of PDL1 on tumor cells is assessed by IHC on tumor tissue achieved by core biopsy. Unfortunately, serial core biopsies are very often not well tolerated by patients due to invasiveness; such a limit represents an obstacle in monitoring the expression on PD-L1 on tumor cells during treatments, such as neoadjuvant chemotherapy.
To avoid this limitation, we aim to test the expression of PD-L1 using CTCs. This alternative approach tests PD-L1 using only blood samples for CTC detection and has many advantages:
- the analysis of PD-L1 on CTCs rather than on tumor samples biopsy may reveal important information on the mechanism of tumor progression and dissemination. Indeed, CTCs may represent the cell populations that probably will develop distant metastases therefore studying them may provide us new vital pieces of knowledge;
- PD-L1 testing on tissue from core biopsies could have sampling limits that serial liquid biopsies could overcome;
- it is easier to propose serial liquid biopsies to patients being better tolerated - rather than serial core biopsies. We think this aspect has an important impact on a study design since we have the duty of trying to improve patient quality of life both as cancer researchers and clinicians.
We aim to investigate the expression PD-L1 on CTCs of patients with early breast cancer and to evaluate their role as surrogate marker of pathologic complete response.
Furthermore, the expected high expression of PD-L1 in BRCA1/2 mutated breast cancers, independently from histological subtypes, might provide evidence for a new key player in the biology of these cancers, thus providing the rationale for treatment combination.
We aim with this study to add an important step in qualifying liquid biopsy as an integral part of the precision medicine approach in the management of breast cancer patients and help to identify preferential targets for new therapeutic approaches.