RESUMO
Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC.
RESUMO
OPINION STATEMENT: Systemic neoadjuvant chemotherapy is utilized along with surgery and radiotherapy for the management of patients with locally advanced breast cancer. The backbone of current chemotherapy regimens include anthracyclines and taxanes given either sequentially or concurrently for up to 8 cycles. Neoadjuvant treatment benefits include in vivo assessment of response to treatment with reduction in the extent of primary and regional metastases. Neoadjuvant chemotherapy for operable breast cancer is used in women who desire breast conservation surgery who are not candidates for such treatment at the time of the diagnosis. The use of neoadjuvant treatment in patients, who present with operable breast cancer, shows equivalent survival outcome compared with adjuvant breast cancer treatment. Several prospective studies have evaluated the role of trastuzumab in combination with neoadjuvant chemotherapy in patients with Her2-positive disease. The addition of trastuzumab to neoadjuvant chemotherapy is associated with improvement of the complete clinical and pathological complete response to therapy and significantly improved event-free survival and overall survival. Dual Her2 blockade is emerging as a new approach to improve pathological complete response rates and therefore survival. To date, in triple-negative breast cancer, there are no predictive markers to identify potential treatment targets. Triple-negative patients who achieve a pathological complete response have more favorable outcome compared with those with residual disease following neoadjuvant treatment. The choice of optimal chemotherapy regimen and the duration of treatment have been studied extensively in the neoadjuvant setting. No consensus has been developed thus far. Following work done with anthracycline and CMF treatments in neoadjuvant chemotherapy, recent studies in locally advanced breast cancer focus on the addition of new and target agents. All of these trials are based on well-established regimes used in the adjuvant setting. Successful use of neoadjuvant chemotherapy requires a coordinated multidisciplinary approach.
