Adjuvant Endocrine Therapy: The long and winding road

Adjuvant therapy is based on the concept that cancer may be a systemic disease at the time of diagnosis of an apparently localized presentation.  Micrometastases that arise as a consequence of early dissemination of the disease may remain dormant for an undefined period of time, and result in recurrences over a prolonged period of time, a phenomenon that remains focus of intensive study.  In breast cancer, systemic adjuvant treatment has proven effective both with endocrine therapy and chemotherapy leading to significant improvements in DFS and OS.

However, it is critical to consider that when we indicate adjuvant systemic therapy, we do not know for a fact if that specific patient has micrometastatic disease or not. So, we should expect overtreatment as an underlying consequence of our inability of diagnosing micrometastases.  Conversely, we have been unable to effectively address the question of who are the patients that do not have micrometastases, are cured with local therapy only, and do not require any systemic treatment.

We define patient populations most likely to have a recurrence and select patients according to risk of recurrence.  This is traditionally done on the basis of clinicopathologic factors (tumor size, axillary lymph node involvement, grade, IHC, Ki67, etc.). With time, other factors have been introduced in our risk-defining strategy such as genomic platforms and most recently molecular abnormalities (gBRCA1/2 mutations) that help defining the indication of adjuvant therapies.

Approximately 2 out of 3 patients with BC express hormonal receptors and potentially respond to endocrine therapy (ET) both in the early and metastatic setting.  In general, at least 5 years of ET is recommended for women with stage I-III pre- and postmenopausal HR+ breast cancer. Aromatase Inhibitors are preferred for postmenopausal women while in pre-menopausal patients with high risk of recurrence, dual endocrine therapy with OFS is indicated.

Even though clinicopathologic factors do help identifying risk and we have improved our prognostic abilities with the use of genomic tests, we still need improvements in this area.  In the future, most probably, combination of biomarkers will improve our ability of patient identification.  Duration of endocrine therapy remains an undefined issue. We should recognize that more than half of recurrences occur after the first 5 years of follow up and that we still cannot reliably identify who are the patients that remain at risk after the first 5 years of therapy. Even though we generally suggest treatment continuation to patients with initial high-risk features, this is an area in need of improvements.

Importantly, although ET remains reasonably well tolerated, a significant proportion of patients do complain of bothersome side effects. Adherence and short- and long-term side effects management are important areas to consider.

For decades, blocking the ER pathway with AI or Tamoxifen has led to important benefits in the metastatic setting.  However, it is naïve to believe that a complex disease like cancer will be optimally controlled or even cured with just one single approach. Combination regimens will be the rule for a least a proportion of patients with high risk disease. Better understanding of the underlying biology has allowed us to identify pathways that interact with endocrine signaling and that when blocked concomitantly result in much better clinical outcomes. The clearest successful example of this concept is the introduction of the adjuvant Abemaciclib combination with an AI in the monarchE trial including high risk patients.