Clinical Perspectives in Addressing Unsolved Issues in (Neo)Adjuvant Therapy for Primary Breast Cancer

Abstract

The treatment of primary breast cancer has evolved over the past 50 years based on the concept that breast cancer is a systemic disease, with the escalation of adjuvant and neoadjuvant therapies and de-escalation of breast cancer surgery. Despite the development of these therapies, recurrence with distant metastasis during the 10 years after surgical treatment is observed, albeit infrequently. Recent advances in genomic analysis based on circulating tumor cells and circulating tumor DNA have enabled the development of targeted therapies based on genetic mutations in residual tumor cells. A paradigm shift involving the application of neoadjuvant chemotherapy (NAC) has enabled the prediction of treatment response and long-term prognoses; additional adjuvant chemotherapy targeting remaining tumor cells after NAC improves survival. The activation of antitumor immunity by anticancer agents may be involved in the eradication of residual tumor cells. Elucidation of the manner in which antitumor immunity is induced by anticancer agents and unknown factors, and the overcoming of drug resistance via the targeted eradication of residual tumor cells based on genomic profiles, will inevitably lead to the achievement of 0% distant recurrence and a complete cure for primary breast cancer.

Keywords: adjuvant therapy; antitumor immunity; breast cancer; neoadjuvant therapy; residual tumor cells.

Figure 1

A time course for distant metastasis after adjuvant and neoadjuvant therapies in patients with breast cancer. Although primary lesions and axillary lymph nodes can be removed maximally by surgical treatment, the minimal presence of residual tumor cells, as assessed by CTC and ctDNA analyses, contributes to recurrence and distant metastasis. Genomic mutations in primary tumors can cause resistance to anticancer agents and endocrine therapy. The remaining tumor cells with genomic mutations cause the clonal evolution of tumor growth, leading to distant metastasis. The use of adjuvant therapy in combination with endocrine therapy and CDK4/6 inhibitors may improve survival. After neoadjuvant chemotherapy, additional adjuvant chemotherapy targeting residual tumor cells improves survival. CTC, circulating tumor cell; ctDNA, circulating tumor DNA; CDK, cyclin-dependent kinase; HER-2, human epidermal growth factor receptor 2; TN, triple negative.

Figure 2

A scheme for the understanding of residual tumor cells’ causing of distant recurrence after neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy in patients with breast cancer. When a patient responds to NAC, the anticancer treatment induces a clinical complete response (cCR) followed by a pathological complete response (pCR). Anticancer agent-induced (immunogenic) cell death evokes the establishment of antitumor immunity, which eventually prevents the regrowth of residual tumor cells. If immunogenic antitumor immunity is not established successfully, meaning that it fails to eradicate residual tumor cells, the presence of these cells at the macro and molecular levels may contribute to distant metastasis. The details of the manner in which antitumor immunity is gained after NAC are not clear. Adjuvant chemotherapy aims to cure breast cancer by targeting residual tumor cells and eradicating them via the cytotoxic effects of anticancer agents. Whether these processes require the induction or gain of antitumor immunity by anticancer agents used in adjuvant chemotherapy is unclear. Drug sensitivity and the establishment of antitumor immunity via anticancer drug therapy may be important for the achievement of a complete cure for primary breast cancer.

Figure 3

Hypothesized relationships of tumor volume to cell death and antitumor immunity after (neo)adjuvant chemotherapy for primary breast cancer. Decreased tumor volume is hypothesized to be related synergistically to increased cell death and the induction of antitumor immunity. The degree of increased cell death is almost parallel to the degree of antitumor immunity activation. In neoadjuvant chemotherapy responders, tumor shrinkage correlates with the rate of cell death and the induction of antitumor immunity, with the maximum response consisting of clinical complete response leading eventually to pathological complete response. The induction of antitumor immunity leads to the gain of such immunity, with the complete eradication of tumor cells and prevention of distant metastasis. The failure to gain antitumor immunity may allow residual tumor cells to survive, leading to distant metastasis. The gain of antitumor immunity may be regulated by unknown factors.

Figure 4

The activation of the hypothalamic-pituitary-adrenal (HPA) axis due to surgical stress and the use of certain anesthetic techniques may be involved in the increased distant recurrence of breast cancer. Surgical stress and general anesthesia (GA) under mechanical ventilation with tracheal intubation activate the HPA axis and increase neuroendocrine mediators, such as cortisol, leading to immunosuppression that increases the distant metastasis of breast cancer. Opioid-induced immunosuppression is also involved in the increase in distant recurrence. The development of distant metastasis to the bone, lung, liver, and other parts of the body from residual tumor cells is observed after surgical treatment. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone.