Abstract
BackgroundResidual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC.MethodsThe Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/− durvalumab +/− oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk.Discussioncombination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates.Trial registrationtrial registered on ClinicalTrials.gov (NCT03875573) on March 14th, 2019.
Highlights
Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes
The rates of pathological complete response with neo-adjuvant chemotherapy (NACT), are poor for luminal B compared to the non-luminal subtypes: 15% in luminal B versus 46% in HER2 positive BC and 45% in triple negative BC (TNBC) [2,3,4]
estrogen receptor (ER)-positive is defined as having an immunohistochemistry (IHC) of 10% or more and/or and Allred score of 3 or more HER2-negative is defined as having an IHC of 0 or 1+ without in-situ hybridization (ISH) testing OR IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells [without IHC]; note: a IHC of 3+ is always considered HER2 positive, independently of the ISH result
Summary
Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. The rates of pathological complete response (pCR) with neo-adjuvant chemotherapy (NACT), are poor for luminal B compared to the non-luminal subtypes: 15% in luminal B versus 46% in HER2 positive BC and 45% in triple negative BC (TNBC) [2,3,4]. Strategies to prime immune responses seem critical to increase clinical benefit of immunotherapy in non-inflamed cancer types [8,9,10]. An area of active research is how to convert non-inflamed cancers into inflamed cancers, leveraging the effects of local and/or systemic treatment and increasing pCR rates with immunotherapy combinations
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