Saying goodbye to primary endocrine resistance for advanced breast cancer?
Abstract
Cyclin-dependent 4/6 is a vital resistance pathway as it has a targetable treatment. According to the European Society for Medical Oncology (ESMO) guidelines, as an expert opinion, primary endocrine resistance is defined as relapse while on the first 2 years of adjuvant endocrine treatment (ET), or progressive disease (PD) within first 6 months of first-line ET for advanced breast cancer (ABC), while on ET. This definition is based on endocrine monotherapy used in the adjuvant and metastatic process. It is obvious that the concept of primary endocrine resistance defined by ESMO for adjuvant is still appli- cable. However, the concept of primary endocrine resistance defined for metastatic disease is no longer viable. We think that a new concept such as “primary ET + CDK 4/6 resistance” should be defined. Because the progression-free survival achieved with monotherapies in metastatic disease does not exceed 12 months, this period has reached 27 months with ET + CDK 4/6 inhibitors. We think that the 6 months defined for primary endocrine resistance in patients with ABC during endocrine monotherapy is too short for patients receiving ET + CDK 4/6 inhibitor. Therefore, the concept of novel primary ET + CDK 4/6 inhibitor resistance should be created to be used in patients with ABC. The concept of ET + CDK 4/6 inhibitor resistance to be defined may be used in the stratification of clinical trials aimed at determining subsequent treatments in patients who progressed under ET + CDK 4/6 inhibitor.
Keywords : Endocrine resistance · Cyclin-dependent kinase · Breast cancer
The estrogen receptor pathway, which plays an essential role in breast cancer formation, is closely related to disease pro- gression in breast cancer [1]. The treatment of hormone-pos- itive Her2-negative metastatic breast cancer without visceral crisis is based on endocrine therapies (ET) [1]. Among the endocrine treatments, aromatase inhibitors, selective estro- gen receptor modulators (SERMs), and selective estrogen receptor downregulator (SERD) were used as monotherapy in first-line for a long time [1]. One of the most important problems that clinicians face in patients undergoing ET is ET resistance [1]. Many pathways cause endocrine treat- ment resistance [1]. Cyclin-dependent 4/6 is a vital resist- ance pathway as it has a targetable treatment [1]. Indeed, with the initiation of Cyclin-dependent 4/6 inhibitors (CDK 4/6Is), successful results were obtained in patients with HR- positive Her2-negative advanced breast cancer (ABC) [1]. The addition of CDK 4/6I to ET is the standard of care in patients with HR-positive Her2-negative ABC without vis- ceral crisis [1]. The confusing situation here is what should be the subsequent treatment in patients progressing under ET + CDK 4/6Is.
In CDK 4/6I trials, previous endocrine sensitivity or primary endocrine resistance were among the stratifica- tions [2]. According to the European Society for Medical Oncology (ESMO) guidelines, as an expert opinion, pri- mary endocrine resistance is defined as relapse while on the first 2 years of adjuvant ET, or progressive disease (PD) within first 6 months of first-line ET for ABC, while on ET. This definition is based on the experience of endocrine monotherapy used in the adjuvant and metastatic process. It is obvious that the concept of primary endocrine resistance defined by ESMO for adjuvant is still applicable, since ET monotherapy is the standard of care in adjuvant therapy for HR-positive HER2-negative breast cancer patients. How- ever, we think that the concept of primary endocrine resist- ance defined for metastatic disease is no longer viable. For example, subgroup analyses of the study investigating the efficacy of Alpelisib in patients with PIK3CA-mutant HR- positive Her2-negative breast cancer revealed that alpelisib was not effective in primary endocrine-resistant patients [3]. However, using 6 months as the primary endocrine resist- ance period for patients receiving prior CDK 4/6Is, which constitutes approximately 5–6% of this study [3], may have affected the results of the subgroup analysis.
We think that a new concept such as “primary ET + CDK 4/6I resistance” should be defined to not experience similar confusing situations in subsequent studies after CDK 4/6Is. Because the progression-free survival achieved with mono- therapies in metastatic disease does not exceed 12 months, this time has reached 27 months with ET + CDK 4/6Is [2]. We think that the 6 months defined for primary endocrine resistance in patients with ABC during endocrine mono- therapy is too short for patients receiving ET + CDK 4/6Is. Therefore, the concept of novel primary ET + CDK 4/6I resistance should be created instead of the old primary endocrine resistance to be used in patients with ABC. We believe that the concept of ET + CDK 4/6I resistance to be defined can be used in the stratification of clinical studies aimed at determining subsequent treatments BLU-222 in patients who progressed under ET + CDK 4/6Is.