Escalation of neoadjuvant therapy in triple-negative breast cancer—balancing effectiveness and toxicities

Triple-negative breast cancer (TNBC) is defined by the lack of overexpression of the estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) and is to date the most aggressive subtype in breast cancer. Compared to other subtypes, it is associated with higher recurrence rates especially in the first 5 years after diagnosis and typically occurs in women of younger age [1]. Due to its biologically and clinically heterogeneity, treatment remains a challenging field with only chemotherapy as an effective treatment option over the last decades. However, new therapeutic options such as poly(ADP-ribose) polymerase (PARP) inhibitors, antibody–drug conjugates, and immune checkpoint inhibitors have revolutionized the treatment field of TNBC. The association between tumor cells and their microenvironment has been better understood and led to the definition of an ecosystem of TNBC. Here, we can differentiate between cancer-cell intrinsic factors such as genomic, transcriptomic or proteomic features and extrinsic factors describing the tumor microenvironment [2].

Neoadjuvant treatment of early TNBC is the gold standard with its cure as the primary goal. In patients with stage II TNBC, the neoadjuvant combination of systemic chemotherapy and immunotherapy with the programmed death (PD)-1-inhibitor pembrolizumab based on the results of the KEYNOTE-522 study is currently standard of care. All patients derived a benefit from the addition of immunotherapy independent of tumor size or nodal status. However, nearly 50% of the study population reached a pathologic complete response (pCR) associated with an improved event-free survival with chemotherapy alone [3]. The question of who needs both is still a matter of debate and of great importance in the light of immunotherapy-related side effects.

There is currently still a lack of reliable biomarkers to identify responders to immunotherapy. Although TNBC is associated with the highest immune activation across all subtypes, there is also immunological heterogeneity which may lead to poor response to neoadjuvant immunotherapy in a subgroup of patients [4]. The tumor ecosystem plays a key role in treatment response. Higher tumor mutational burden, high neoantigen loads or proliferative fractions of major histocompatibility complex (MHC) I for instance are strong predictors for response to immunotherapy. Increased subclonal diversity or decreased copy number instability is related to poor treatment response [5]. Wang et al. investigated the impact of multicellular spatial organization on response in the neoadjuvant NEOTRIP randomized controlled trial. Interestingly, they showed for the first time in this setting that cell phenotype, activation state, and spatial location are closely connected to each other and influence the effect of immune checkpoint inhibitors in early stages [6]. Another tool to differentiate between sensitive and resistant tumors might be the assessment of circulating tumor DNA (ctDNA) during neoadjuvant treatment. It could be shown that ctDNA dynamics during neoadjuvant chemotherapy predict clinical outcomes and ctDNA negativity is associated with improved survival despite having residual cancer after neoadjuvant treatment [7].

If we treat everyone the same way one question remains: what is the toxicity that we impose on our patients? The most common treatment-related adverse events ≥ 20% in KEYNOTE-522 in both arms were nausea, alopecia, anemia, neutropenia, fatigue, or diarrhea—all known as typical chemotherapy-associated. The most common immune-mediated adverse events were infusion reactions, hypothyroidism, severe skin reactions, hyperthyroidism, adrenal insufficiency, or pneumonitis [8]. Most adverse events can be treated successfully with corticosteroids. Nonetheless, chronic or irreversible toxicity might be more common than initially thought and can lead to the need of permanent hormone replacement therapy. Especially hypophysitis, thyroiditis, and adrenal insufficiency have the highest probability to develop into chronic toxicity [9]. However, some of the immune-related adverse events can end fatally which, therefore, has to be taken into account when informing our patients. Myocarditis, myositis, neurologic toxicity, or pneumonitis which rarely occur have the highest fatality rates [10].

There is also evidence that there is an association between immune-related toxicities and clinical benefit. A meta-analysis of 51 studies on different tumor types but with lung cancer as the major tumor type showed a positive association between developing immune-related side effects and progression-free or overall survival. These effects were observed regardless of disease site, type of checkpoint inhibitor, or immune-related adverse event [11]. One of the major aims when treating our younger female patients should be preserving their fertility. The effect of immunotherapy on ovarian function and fertility is still unclear but trials focusing on this important issue are on the way. Winship et al. evaluated the effect of immune checkpoint inhibitors on the ovary in mice. They showed that immune checkpoint inhibitors not only reduce the ovarian follicular reserve but also worsen the capability of oocytes in maturation and ovulation [12]. Therefore, it should be the highest priority to investigate preventive strategies and offer fertility preservation to all of our patients with an unfulfilled desire to have a child. Similar to reliable and routinely biomarkers for response to immunotherapy we also lack any biomarkers for predicting treatment-related side effects. Female sex, pre-existing autoimmune conditions, a higher neutrophil/lymphocyte ratio or higher amounts of circulating cytokines have been associated with increased immune-related adverse events in the literature [13‐16]. Bukhari et al. performed single-cell RNA sequencing of circulating T cells from cancer patients. They interestingly described that different populations of T cells are associated with different immune-related adverse events leading to the hypothesis that these cells have the potential to serve as biomarkers predicting immune-related toxicity [17].

Despite the fascinating data on significant improvement in survival of cancer patients by the effect of immune checkpoint inhibitors leading to a new era in cancer medicine, there are still other factors influencing our patients’ lives and response to cancer treatment. A randomized trial of exercise and nutrition on chemotherapy completion and pathologic complete response in women with breast cancer was published in 2023. The authors showed that a home-based exercise and nutrition intervention was associated with higher pCR in patients with HER2-negative breast cancer [18]. Finally, the emotional distress of our patients plays an important role during cancer treatment. A post hoc analysis evaluated the association between pretreatment emotional distress and clinical response to neoadjuvant immune checkpoint inhibition in melanoma patients. Here, emotional distress was significantly associated with worse response to immunotherapy and decreased relapse-free and distant metastasis-free survival [19].