NeoCARD: Anthracycline-Free Neoadjuvant Chemoimmunotherapy in Triple-Negative Breast Cancer Patients

Clinical trial participation among patients with cardiac co-morbidities is limited, creating challenges for oncologists managing aggressive cancers like Triple Negative Breast Cancer (TNBC) in this demographic. At MUSC and its affiliated rural sites, a significant portion of our patient population presents with complex medical histories and co-morbidities that increase their risk for anthracycline-induced cardiotoxicity. Therefore, proposing a dedicated study focused on patients with pre-existing cardiomyopathy or those at high risk for cardiotoxicity-using a non-anthracycline-based regimen-is both timely and essential.

Rationale for Using Paclitaxel, and Carboplatin with Immunotherapy:

It is estimated that around 60% of TNBC patients exhibit a "BRCAness" phenotype, which mirrors the clinical characteristics of tumors with BRCA mutations. Consequently, the use of DNA-damaging agents, like platinum-based therapies, has gained prominence as a viable treatment option for these patients. Several studies have demonstrated that adding carboplatin to neoadjuvant chemotherapy regimens improves the pCR rates in TNBC patients. While some trials have also shown improvements in disease-free survival, others have not observed this benefit. Notably, a recent study from India highlighted an overall survival advantage, specifically in TNBC patients under the age of 50, when carboplatin was included in their treatment.

Platinums have also been shown to modulate the immune system and cause immunogenic mediated cell death whereby they can increase major histocompatibility complex (MHC) class I expression on cancer cells thus promoting T-cell activation. Although platinums on their own could induce an immune response, a combination with taxanes like paclitaxel has been shown to augment this response as evidenced by decreasing T regulatory cells and increasing the proportions of T-helper cells and natural killer cells. In a mouse study looking at combining cisplatin with paclitaxel and immunotherapy, it was found that chemotherapy enhanced immune-mediated cancer cell death by decreasing intratumoral T regulatory cells and increasing the recruitment of cytokine-induced killer cells.

Beyond its direct cytotoxic activity as a microtubule-stabilizing agent, paclitaxel exerts potent immunomodulatory effects that make it an attractive chemotherapeutic backbone for combination with immune checkpoint inhibitors in triple-negative breast cancer (TNBC). Three key preclinical mechanisms support this rationale. First, paclitaxel functions as a Toll-like receptor 4 (TLR4) agonist by directly binding the MD-2 accessory molecule of the TLR4 complex on myeloid cells, mimicking bacterial lipopolysaccharide and activating TLR4/TRIF/IRF3 signaling to induce type I interferons and CTL-attracting chemokines within the tumor microenvironment; this TLR4 activation reprograms tumor-associated macrophages from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype, enhances antigen cross-presentation, and is associated with upregulated IFNα/IFNγ signaling in paclitaxel responders. Second, paclitaxel enhances dendritic cell maturation and antigen-presenting function through TLR4 signaling, increasing expression of co-stimulatory molecules (CD80, CD86, CD40), MHC class II, and IL-12, and generating CD8⁺ T cells with markedly increased lytic activity against tumor cells; in vivo, paclitaxel treatment expands antigen-specific, IFNγ-secreting CD8⁺ T cells in vaccine-draining lymph nodes, an effect abrogated by TLR4 blockade. Third, paclitaxel induces immunogenic cell death, with treated tumor cells exposing calreticulin and releasing HMGB1 and other DAMPs that promote phagocytic uptake and TLR4-dependent innate immune activation, while cytoplasmic DNA from dying cells triggers cGAS/STING/IRF3 signaling and further type I interferon and chemokine production, functionally mimicking an in situ vaccination. Collectively, TLR4-mediated macrophage reprogramming, enhanced dendritic cell maturation, and immunogenic cell death converge to convert the tumor microenvironment from immunologically "cold" to "hot," creating optimal conditions for PD-1/PD-L1 blockade. In TIL-high TNBC, where a pre-existing adaptive immune response is present, paclitaxel amplifies this endogenous immunity, providing a strong mechanistic rationale for its use as the chemotherapeutic backbone in a de-escalated chemoimmunotherapy regimen.

Rationale for Weekly Paclitaxel Over Taxotere:

In the ECOG E1199 trial, 4,954 patients with stage II-III breast cancer received AC×4 followed by randomization to paclitaxel or docetaxel given either every 3 weeks or weekly, in a 2×2 factorial design with DFS as the primary endpoint. After 12.1 years of follow-up, both weekly paclitaxel and every-3-week docetaxel produced significantly superior DFS and numerically better OS compared with every-3-week paclitaxel, whereas the other experimental arm (weekly docetaxel) did not. In the triple-negative subset (n≈1,025), weekly paclitaxel emerged as the most effective regimen, yielding a ~30% relative reduction in recurrence and death (HR 0.69 for both DFS and OS) and the highest 10-year DFS (69%) and OS (75%) among the four taxane schedules.

In terms of chemotherapy-related toxicities, every 3-week docetaxel was associated with higher levels of grade 4 toxicities than weekly paclitaxel 50% versus 4% respectively and most of the side effects are related to grade 4 neutropenia (46% vs 2%), febrile neutropenia (16% vs 1%), grade 3-4 stomatitis, fatigue, and myalgias. Conversely, the paclitaxel group had a higher level of grade 3 or 4 neuropathy of around 8% versus 4%. Unique to docetaxel, patients can also experience fluid retention syndrome often requiring prophylaxis with corticosteroids. This can manifest as peripheral edema, pleural effusions, ascites, or generalized weight gain. The condition is dose-dependent and typically more pronounced in patients receiving higher cumulative doses of docetaxel. In patients with underlying cardiomyopathy, this adverse effect can pose significant clinical challenges. Therefore, docetaxel is avoided in the NeoCARD study to reduce the risk of neutropenia, fluid overload and cardiac decompensation in this vulnerable population.

Rationale for a 12-Week Regimen:

The effectiveness of regimens featuring weekly taxanes with carboplatin is highlighted in studies like the WSG-ADAPT TN study and the NeoN phase 2 study by Loi et al. A 12-week platinum/taxane/pembrolizumab protocol may achieve pCR in chemo-sensitive patients without the need for prolonged chemotherapy. However, individuals with poor response rates may require extended therapy. Early identification of responders through radiographic methods could enable de-escalation strategies, potentially reducing long-term toxicities such as neuropathy that significantly impact quality of life.

Rationale for Response Adaptive Study Design:

MRI stands out as the most accurate imaging modality for assessing pCR in TNBC patients, with reported accuracy rates exceeding 86%. Therefore, MRI is endorsed as the optimal tool for assessing response by the American College of Radiology (ACR) and the Society of Breast Imaging (SBI).

A prospective, multi-institutional trial (ACRIN 6657/I-SPY TRIAL) demonstrated that MRI-based functional tumor volume measurements after neoadjuvant chemotherapy not only predict pathologic response but also correlate with recurrence-free survival. Specifically, functional tumor volume measured by MRI was shown to predict recurrence-free survival in patients with stage II or III breast cancer undergoing neoadjuvant therapy.

Overall, MRI response adaptive neoadjuvant therapy in breast cancer provides early detection of changes in tumor size and morphology, facilitating prompt assessment of treatment response. Additionally, MRI findings, including alterations in tumor enhancement patterns, can predict pathologic response to therapy, informing decisions about achieving a complete response. These MRI results also guide tailored treatment planning, determining the necessity of additional therapy and suitability for breast-conserving surgery versus mastectomy.